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Real Time Conference Coverage: Advancing Precision Medicine Conference, Afternoon Omics Session Track 2 October 3 2025

Reporter: Stephen J. Williams, PhD

Leaders in Pharmaceutical Business Intellegence will be covering this conference LIVE over X.com at

@pharma_BI

@StephenJWillia2

@AVIVA1950

@AdvancingPM

using the following meeting hashtags

#AdvancingPM #precisionmedicine #WINSYMPO2025

4:20-4:40

Andrea Ferreira-Gonzalez

 

  • APOE was marker for defining a long term survivor and short term survivor for ovarian cancer patients; the markers were in the stroma
  • there is spatial communication between tumor and underlying stroma
  • it is imperative to understand how your multiomics equipment images a tumor area before it laser captures and send to the MS system; can lose a lot of tissue and information based on differences in resolution
  • many of these multiomics systems are validated for the clinic in EU not US
  • multiomics spatial analysis allows you to image protein, metabolite, mRNA expression in the 3 dimensional environment of the tumor (tumor cells and stroma)
  • they are making a human tumor atlas
  • they say a patient who had tumor went home during COVID and took vaccine but got ill with vaccine; but came back to check tumor and tumor had greatly regressed because prevaccine the tumor was immunologically cold and post COVID vaccine any left over tumor showed great infiltration of immune cells

4:40-4:55

Andrea Ferreira-Gonzalez

Aruna Ayer, PhDVP, Multiomics, Innovation and Scientific AffairsBD Biosciences

  • BD Bioscience multiomics platform is modular and can add more omics levels in the platorm
  • for example someone wanted to look at T cells
  • people have added CRISPR screens on the omics platform
  • most people are using single cell spatial omics
  • they have a FACS on their platform too so you can look at single cell spatial omics and sort different cellular populations
  • very comparative to 10X Genomics platform
  • their proteomics is another layer you can add on their platform however with proteomics you can high background notice with spatial proteomics or a limited panel of biomarkers
  • Their OMICS Protein One panels are optimized for biology and tumor type.
  • get high quality multiomics data and proteomics data but in a 3D spatial format
  • developed Cellismo Data Visualization software tool

4:55-5:10

Andrea Ferreira-Gonzalez

Harsha Gowda, PhDSenior Principal Scientist, Director, Research & Lab Operations, Signios Bio

Signios Biosciences (Signios Bio) is the US-based arm of MedGenome, a global leader in genetic testing services, genomics research, and drug discovery solutions.

Signios Bio is a multiomics and bioinformatics company dedicated to revealing the intricate signals within biological data. We leverage the power of multiomics—integrating data from genomics, transcriptomics, proteomics, epigenomics, metabolomics, and microbiomics—to gain a comprehensive understanding of disease biology. Our AI-powered bioinformatics platform allows us to efficiently analyze these complex datasets, uncovering hidden patterns and accelerating the development of new therapies and diagnostics.

Through the integration of cutting-edge multiomics technologies, advanced bioinformatics, and the expertise of world-class scientists, we enable researchers and clinicians with comprehensive, end-to-end solutions to improve drug discovery and development and advance precision medicine.

As part of MedGenome, we have access to real-world evidence (RWE) from global research networks across the US, Europe, Asia, Africa, Middle East, and Latin America. This access enables us to work with our partners to uncover insights that can lead to new biomarkers and drug targets, ensuring that precision medicine is inclusive and effective for all.

https://www.signiosbiolcom 

  • their platform can do high throughput analysis of patient tumors (like gallbladder cancer) analyzing mutational spectrum with high dimensionality
  • they can integrate genomic and transcriptomics data to reveal multiple pathways affected in patient data
  • have used their platform to investigate spatial omics in lung cancer

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Hypercortisolism in Difficult-to-Control Cardiometabolic Conditions: Type 2 Diabetes and Hypertension

Reporter: Aviva Lev-Ari, PhD, RN

Do you have patients who are adherent with their medications yet still have uncontrolled type 2 diabetes (T2D) and hypertension? Data from the CATALYST trial presented in 2024 found that 24% of patients with difficult-to-control T2D had hypercortisolism. In a subanalysis of the CATALYST trial, drug-resistant hypertension was present in a third of patients with difficult-to-control T2D. Therefore, we are beginning to understand that excess cortisol could be driving difficult-to-control cardiometabolic conditions. Learn how to screen patients who may have unrecognized hypercortisolism in this collection of education activities created by leading experts in the fields of cardiology, nephrology, diabetes, and endocrinology.

SOURCE

https://www.medscape.org/sites/advances/hypercortisolism?sso=true&uac=93761AJ&src=mkmcmr_driv_clinad_mscpedu

Read Full Post »

10th annual World Medical Innovation Forum (WMIF) Monday, Sept. 23–Wednesday, Sept. 25 at the Encore Boston Harbor in Boston

Dr. Aviva Lev-Ari, PhD, RN, Founder

Leaders in Pharmaceutical Business Intelligence Group, LLC, Doing Business As LPBI Group, Newton, MA

will be in attendance

covering this event in REAL TIME for PharmaceuticalIntelligence.com and WMIF organizers

#WMIF2024

@Pharma_BI

@AVIVA1950

CLAIMER: Live coverage in REAL TIME on X.com for 9/23/2024

my two X.com accounts had exceeded tweeting volume capacity and were inactivated to verify if I am a person or a BOT. Account authentication reported SOmething went wrong, try later.

  • 9/23/2024 contacted Customer Services at X.com for reactivated these two accounts

 

For Speaker’s quotes on 9/23/2024 from 4PM EST to end on the day

  • see below on WordPress.com by Date, Time, Session Name and Speaker Name

For Speaker’s quotes on 9/24/2024 from 8AM to 5:30PM

  • see below on WordPress.com by Date, Time, Session Name and Speaker Name

For Speaker’s quotes on 9/25/2024 from 8AM to 12:35PM

  • see below on WordPress.com by Date, Time, Session Name and Speaker Name

UPDATE on reactivation of handles on X.com will be posted, here.

Usage of X.com will resume after Handle reactivation by X.com

 

UPDATED on 9/26/2024

Unmet Needs Panel

https://www.youtube.com/watch?v=e6hk7yavBzk

100+ Mass General Brigham Leading Experts Identify

Top Unmet Needs in Healthcare

Project from Harvard Medical School-affiliated clinicians and scientists in the Mass General Brigham healthcare system stimulates new consideration, urgency regarding

innovation in life sciences, healthcare

Top 10 List Announced at World Medical Innovation Forum

BOSTON, MA September 25, 2024 – Some of the most vexing challenges and transformational opportunities in healthcare are included in a new list, “Top Unmet Needs in Healthcare” released by leading experts at Mass General Brigham. Identified by more than 100 Harvard Medical School faculty at Mass General Brigham, the findings range from the need to expand and accelerate rare disease treatment, to the coming “gray tsunami” of aging patients and the implications for patient care, delivery, and technology. The project, revealed at the 10th annual World Medical Innovation Forum, is meant to stimulate new consideration and urgency regarding solving and advancing these issues for improved patient care.

Views from Leading Clinicians, Researchers, and Practitioners in Academic Medicine

The Top Unmet Needs emerge from structured one-on-one discussions with more than 100 Harvard faculty who practice medicine and conduct research at Mass General Brigham, the largest hospital system-based research enterprise in the U.S., with an annual research budget exceeding $2 billion, and five of the nation’s top hospitals according to US News & World Report.

Through one-on-one discussions with these key opinion leaders from diverse clinical and research fields, and subsequent analyses by internal teams of experts, Mass General Brigham has identified the following top 10 unmet clinical needs:

#1. Preparing for the ‘Gray Tsunami’

The need for better tools and therapies aimed at caring for geriatric populations and maintaining geriatric independence, with a particular focus on expanded hospital-at-home capabilities, and the need to better understand the pathways that lead to chronic and acute disease in geriatric patients to enable better and more proactive treatment.

#2. Defining and Maintaining Brain Health

The need for a model of brain health and neurological care that clearly defines not only what brain health is but also integrates our current understanding of the mechanisms and phases of neuroinflammatory and neurodegenerative diseases; enables better and earlier diagnoses and treatment; and propels the development of therapies that target these mechanisms and phases.

#3. A Paradigm Shift in Cancer Treatment

The need for a new framework for therapeutic development in cancer that is focused on improving curability as opposed to an exclusive focus on the development of drugs for metastatic disease. This

framework also requires effective tools for early-stage cancer detection across the board in all cancers, but especially in lung, ovarian, pancreatic, and GI cancers (esophagus, stomach and colon).

#4. Targeting Fibrosis, a Shared Culprit in Disease

The need for therapeutics that target fibrosis (tissue scarring), which is responsible for a significant percentage of deaths worldwide, representing diseases of the lung, liver, kidney, heart, and skin.

#5. New Approaches for Infectious Disease in a Changing World

The need for novel strategies for the rapid diagnoses, treatment, and even prevention of antibiotic-resistant infections, and the need for the next generation of globally deployable vaccines to enable pandemic preparedness.

#6. Striving for Equity in Healthcare

The need to radically rethink how, when, and where patients interact with healthcare services to optimize healthcare access and efficiency without diminishing its effectiveness, and to proactively meet the needs of currently underserved populations.

#7. Riding the Wave of Clinical Data

The need to expand the scope of available clinical data to include historically understudied populations (including women) and to model and implement a cohesive, dynamic data “stream,” which flows as patients do between the different phases of health and clinical care, enabling comparisons of patients to their previously healthy selves and the development of AI/ML approaches to harness these data to improve diagnosis, prognosis, and treatment.

#8. A Systems-Level View of Human Disease

The need to rethink how we understand and treat disease — not only from an organ-specific standpoint but from a whole-body, systems-level view — and to fully elucidate the roles that inflammation and immune pathways play in autoimmune and infectious diseases and their effects on chronic and acute diseases in diverse human systems, such as the cardiovascular/circulatory and nervous systems.

#9. A New Approach to Psychiatric Disease

The need for novel treatments for psychiatric disease, improved biomarkers and minimally invasive and ambulatory ways of measuring them, and more productive interactions with industry to advance new therapies to the clinic. This includes hybrid therapies (therapies that combine elements such as talk therapy, novel biomarkers, and pharmacological treatments) as well as new diagnostic and treatment modalities, such as psychedelic therapeutics and precision psychiatry.

#10. Charting a Course in Rare Disease Treatment

The need for viable treatments for the 7,000 identified rare diseases, especially the roughly 70% of such diseases that are genetic and the effects of which are first observed in early childhood.

The Unmet Needs list also include the following honorable mentions which rose to significant rankings in the analysis:

  • Driving Innovation in Chronic Disease: Improved Diagnosis, Treatment, and Prevention
  • A New Era of Obesity Medicine
  • A New Generation of Pain Treatments
  • Unlocking Novel Treatments for the Skin

Overarching Themes

Addressing unmet clinical needs involves solving a number of common challenges, including commercialization hurdles, regulatory considerations, and funding. The Mass General Brigham project identified overarching themes to help address these challenges and support innovation across multiple sectors. These include:

  • Taking a systems view of human disease and the practice of system-medicine
  • Developing a global view of infectious disease, including antimicrobial resistance
  • An expansion in high-quality, real-world data that closes gaps in current data (particularly for women and other underserved populations) and ensures that data sets are sufficiently enabling for AI/ML
  • Improving health and healthcare across key populations, including geriatrics and rare genetic disease
  • Addressing major diseases of the brain, including both neurodegenerative and neuropsychiatric conditions; these include Alzheimer’s disease, Parkinson’s disease, ALS, as well as psychiatric and mental health disorders
  • Opening an era of precision medicine across disease areas that includes early diagnosis, treating staged disease, and biomarker discovery and utilization

Panel co-chairs José Florez, Physician-in-Chief and Co-Chair of the MGB Department of Medicine and the Jackson Professor of Clinical Medicine at Harvard Medical School, and Bruce Levy, Physician-In-Chief and Co-Chair of the MGB Department of Medicine and the Parker B. Francis Professor of Medicine at Harvard Medical School, noted how the observations of a broad and representative set of faculty help illuminate the innovation landscape ahead.

“As a leader in patient care and healthcare innovation, our goal is to build on the legacy of research and discovery that has shaped the hospitals of the Mass General Brigham healthcare system for more than a hundred years, and continue to bring breakthroughs forward that can help solve pressing needs,” said Dr. Florez.

Dr. Levy added that “This is a roadmap for the future that can inform discussions happening throughout the healthcare and investment ecosystem regarding the future of medicine.”

More than 2000 decision-makers from healthcare, industry, finance and government attended the World Medical Innovation Forum this week in Boston. A premier global event, the Forum highlights leading innovations in medicine and transformative advancements in patient care.

###

About Mass General Brigham

Mass General Brigham is an integrated academic health care system, uniting great minds to solve the hardest problems in medicine for our communities and the world. Mass General Brigham connects a full continuum of care across a system of academic medical centers, community and specialty hospitals, a health insurance plan, physician networks, community health centers, home care, and long-term care services. Mass General Brigham is a nonprofit organization committed to patient care, research, teaching, and service to the community. In addition, Mass General Brigham is one of the nation’s leading biomedical research organizations with several Harvard Medical School teaching hospitals. For more information, please visit massgeneralbrigham.org.

Contact: Tracy Doyle Mass General Brigham Innovation

(262) 227-5514

Tdoyle5@mgb.org

SOURCE

From: “Doyle, Tracy” <tdoyle5@mgb.org>
Date: Thursday, September 26, 2024 at 10:19 AM
Cc: “Card, Matthew” <matthew.card@bofa.com>
Subject: Unmet Needs in Healthcare — Press Release and link to panel

 

@@@@@@@

Invitation as MEDIA

From: “Doyle, Tracy” <tdoyle5@mgb.org>
Date: Wednesday, August 14, 2024 at 4:04 PM
Cc: “Doyle, Tracy” <tdoyle5@mgb.org>, “Card, Matthew” <matthew.card@bofa.com>
Subject: Media Invite: World Medical Innovation Forum, Sept. 23-25, Boston — Hundreds of clinical experts, industry, investment leaders

 

Media Invite: World Medical Innovation Forum: Monday, Sept. 23—Wednesday, Sept. 25, Boston

At the intersection of innovation and investment in healthcare

Join Us!

Register Now: WMIF24 Media Registration

Mass General Brigham, one of the nation’s leading academic medical centers, is pleased to invite reporters to the 10th annual World Medical Innovation Forum (WMIF) Monday, Sept. 23–Wednesday, Sept. 25 at the Encore Boston Harbor in Boston. The event features expert discussions of scientific and investment trends for some of the hottest areas in healthcare, including

  • GLP-1s,
  • the cancer care revolution,
  • generative AI-enabled care paths,
  • xenotransplant,
  • community health,
  • hospital at home, and
  • therapeutic psychedelics, among many others.

 

The agenda includes nearly 175 executive speakers from healthcare, pharma, venture, start-ups, and the front lines of care, including many of Mass General Brigham’s Harvard Medical School-affiliated researchers and clinicians who this year will host 20+ focused sessions. Bank of America, presenting sponsor of the Forum, will provide additional expert insights on the investment landscape associated with healthcare innovation.

 

Forum highlights include:

 

1:1 and panel interviews with leading CEOs and government officials including:

  • Stéphane Bancel, CEO, Moderna
  • Albert Bourla, PhD, CEO, Pfizer
  • Marc Casper, CEO, Thermo Fisher
  • Deepak Chopra, MD, Founder, The Chopra Foundation
  • Scott Gottlieb, MD, PhD, Former Commissioner, FDA (2017-2019)
  • Maura Healey, Governor, Commonwealth of Massachusetts
  • David Hyman, MD, CMO, Eli Lilly
  • Haim Israel, Head of Global Thematic Investing Research, BofA Global Research
  • Reshma Kewalramani, MD, CEO, Vertex
  • Anne Klibanski, MD, President and CEO, Mass General Brigham
  • Peter Marks, MD, PhD, Director, Center for Biologics Evaluation and Research, FDA
  • Tadaaki Taniguchi, MD, PhD, Chief Medical Officer, Astellas Pharma
  • Christophe Weber, CEO, Takeda
  • Renee Wegrzyn, PhD, Director, ARPA-H

 

Expert panels including:

  • Oncology’s New Paradigm
  • Gene Therapies for Rare Diseases
  • Future of Metabolic Therapies
  • Digital Transformation
  • Biologic Revolution in Radiotherapies
  • Cell Therapies for Autoimmune Diseases
  • Hospital Venture Funds

 

Leading biotech and venture speakers from companies including:

  • Abata Therapeutics
  • Atlas Venture
  • Be Biopharma
  • Everly Health
  • Flagship Pioneering
  • Fractyl Health
  • MindMed
  • Mirador Therapeutics
  • Regor Therapeutics
  • RH Capital
  • Transcend Therapeutics


Exclusive programming:  

  • First Look – 15 rapid-fire presentations on the latest research from leading Mass General Brigham scientists
  • Un-Met Clinical Needs – 100+ key opinion leaders in healthcare weigh in on the top un-met clinical needs in medicine today
  • Emerging Tech Zone – Hands-on exploration of some of the latest digital and AI-based healthcare technologies

 

Our program keeps growing — explore the current Forum agenda and list of speakers.

FORUM AGENDA

SOURCE

https://2024.worldmedicalinnovation.org/agenda/

Monday, September 23, 2024

    • 7:00 AM – 8:30 AM

      Picasso Foyer

    • 7:00 AM – 5:00 PM

      Rotunda

    • 8:00 AM – 10:00 AM

      Picasso Ballroom

      First Look

      First Look: 14 rapid fire presentations

      Moderators

      Giles Boland, MD

      President, Brigham and Women’s Hospital and Brigham and Women’s Physicians Organization;

      Philip H. Cook Distinguished Professor of Radiology, Harvard Medical School

      Marcela del Carmen, MD

      President, Massachusetts General Hospital and Massachusetts General Physicians Organization (MGPO);

      Executive Vice President, Mass General Brigham;

      Professor of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School

      Presenters

      Natalie Artzi, PhD

      Associate Professor of Medicine, Brigham and Women’s Hospital & Harvard Medical School

      Yolonda Colson, MD, PhD

      Chief, Division of Thoracic Surgery, Massachusetts General Hospital;

      Hermes C. Grillo Professor of Surgery, Harvard Medical School

      Nobuhiko Hata, PhD

      Director, Surgical Navigation and Robotics Laboratory, Brigham and Women’s Hospital;

      Professor of Radiology, Harvard Medical School

      John Hanna, MD, PhD

      Associate Professor, Brigham and Women’s Hospital & Harvard Medical School

      Leigh Hochberg, MD, PhD

      Director of Neurotechnology and Neurorecovery, Massachusetts General Hospital;

      Senior Lecturer on Neurology, Harvard Medical School

      Daphne Holt, MD, PhD

      Director of the Resilience and Prevention Program, Massachusetts General Hospital;

      Associate Professor of Psychiatry, Harvard Medical School

      Ole Isacson, MD-PhD

      Founding Director, Neuroregeneration Research Institute, McLean Hospital;

      Professor of Neurology and Neuroscience, Harvard Medical School

      Farouc Jaffer, MD, PhD

      Director, Coronary Intervention, Massachusetts General Hospital;

      Associate Professor of Medicine, Harvard Medical School

      Albert Kim, MD

      Assistant Physician, Mass General Cancer Center;

      Assistant Professor, Harvard Medical School

      Vesela Kovacheva, MD, PhD

      Director of Translational and Clinical Research, Mass General Brigham;

      Assistant Professor of Anesthesia, Harvard Medical School

      Mark Poznansky, MD, PhD

      Director, Vaccine and Immunotherapy Center, Massachusetts General Hospital;

      Steve and Deborah Gorlin MGH Research Scholar;

      Professor of Medicine, Harvard Medical School

      Daniel Solomon, MD

      Matthew H. Liang Distinguished Chair in Arthritis and Population Health, Brigham and Women’s Hospital;

      Professor of Medicine, Harvard Medical School

      Scott Solomon, MD

      Director, Clinical Trials Outcomes Center;

      Edward D. Frohlich Distinguished Chair in Cardiovascular Pathophysiology, Brigham and Women’s Hospital;

      Professor of Medicine, Harvard Medical School

      Guillermo Tearney, MD, PhD

      Principal Investigator, Wellman Center for Photomedicine, Massachusetts General Hospital;

      Remondi Family Endowed MGH Research Institute Chair;

      Professor of Pathology, Harvard Medical School

      Raul Uppot, MD

      Interventional Radiologist, Massachusetts General Hospital;

      Associate Professor, Harvard Medical School

      David Walt, PhD

      Professor of Pathology, Brigham and Women’s Hospital;

      Hansjörg Wyss Professor of Biologically Inspired Engineering, Harvard Medical School

    • 10:00 AM – 10:20 AM

    • 10:20 AM – 10:30 AM

    • 10:30 AM – 10:55 AM

      Fireside

      Fireside Chat

      Moderator

      Keith Flaherty, MD

      Director of Clinical Research, Mass General Cancer Center;

      Professor of Medicine, Harvard Medical School

      Panelist

      Albert Bourla, PhD

      Chairman & CEO, Pfizer

    • 11:00 AM – 11:45 AM

Concurrent Events

  • 11:00 AM – 11:45 AM

    Oncology’s New Paradigm

    Moderators

    Keith Flaherty, MD

    Director of Clinical Research, Mass General Cancer Center;

    Professor of Medicine, Harvard Medical School

    Jason Zemansky, PhD

    SMid-Cap Biotech Analyst, BofA Global Research

    Panelists

    Jonathan Carlson, MD, PhD

    Director of Chemistry, Center for Systems Biology, Massachusetts General Hospital;

    Assistant Professor of Medicine, Harvard Medical School

    Gad Getz, PhD

    Director of Bioinformatics, Krantz Center for Cancer Research and Department of Pathology;

    Paul C. Zamecnik Chair in Cancer Research, Mass General Cancer Center;

    Professor of Pathology, Harvard Medical School

    Russell Jenkins, MD, PhD

    Krantz Family Center for Cancer Research, Massachusetts General Hospital;

    Mass General Cancer Center, Center for Melanoma;

    Assistant Professor of Medicine, Harvard Medical School

    Gregory Simon

    President, Simonovation

    Shannon Stott, PhD

    Associate Investigator, Krantz Family Center for Cancer Research and Mass General Cancer Center;

    d’Arbeloff Research Scholar, Massachusetts General Hospital;

    Associate Investigator, Krantz Family Center for Cancer Research Harvard Medical School

  • 11:00 AM – 11:45 AM

    GLP-1s: How Far Will They Go?

    Moderators

    Tazeen Ahmad

    SMid-Cap Biotech Analyst, BofA Global Research

    Fatima Cody Stanford, MD

    Obesity Medicine Physician Scientist, Massachusetts General Hospital;

    Associate Professor of Medicine and Pediatrics, Harvard Medical School

    Panelists

    Caroline Apovian, MD

    Co-Director, Center for Weight Management and Wellness, Brigham and Women’s Hospital;

    Professor of Medicine, Harvard Medical School

    Vanita Aroda, MD

    Director, Diabetes Clinical Research, Brigham and Women’s Hospital;

    Associate Professor, Harvard Medical School

    Paul LaViolette

    Managing Partner & COO, SV Health Investors

  • 11:00 AM – 11:45 AM

    Generative AI: Breakthrough Research and Limitations

    Moderators

    Adam Landman, MD

    Chief Information Officer & SVP, Digital, Mass General Brigham;

    Associate Professor of Emergency Medicine, Harvard Medical School

    Alec Stranahan, PhD

    SMid-Cap Biotech Analyst, BofA Global Research

    Panelists

    Katherine Andriole, PhD

    Director of Academic Research and Education, Mass General Brigham Data Science Office;

    Associate Professor, Harvard Medical School

    David Blumenthal, MD

    Professor of Practice of Public Health and Health Policy, Harvard TH Chan School of Public Health;

    Research Fellow, Harvard Kennedy School of Government;

    Samuel O. Thier Professor of Medicine, Emeritus, Harvard Medical School

    Faisal Mahmood, PhD

    Associate Professor, Brigham and Women’s Hospital & Harvard Medical School

    William Morris, MD

    Chief Medical Information Officer, Google Cloud

  • 11:00 AM – 11:45 AM

    Gene and Cell Therapy’s Unlimited Potential

    Moderators

    Roger Hajjar, MD

    Director, Gene & Cell Therapy Institute, Mass General Brigham

    Charlie Yang, PhD

    Large/SMid-Cap Biotech and Major Pharma Analyst, BofA Global Research

    Nathan Yozwiak, PhD

    Head of Research, Gene and Cell Therapy Institute, Mass General Brigham

    Panelists

    Samarth Kulkarni, PhD

    CEO, CRISPR Therapeutics

    Peter Marks, MD, PhD

    Director, Center for Biologics Evaluation and Research, FDA

    Marcela Maus, MD, PhD

    Director of Cellular Therapy and Paula O’Keeffe Chair in Cancer Research, Krantz Family Center for Cancer Research and Mass General Cancer Center;

    Associate Director, Gene and Cell Therapy Institute, Mass General Brigham;

    Associate Professor, Harvard Medical School

    Joanne Smith-Farrell, PhD

    CEO & Director, Be Biopharma

  • 11:00 AM – 11:45 AM

    Xenotransplant: Game Changing Organ Replacement

    Moderators

    Jason Gerberry

    Specialty Pharma and SMid-Cap Biotech Analyst, BofA Global Research

    Joren Madsen, MD, PhD

    Director, MGH Transplant Center;

    Paul S. Russell/Warner-Lambert Professor of Surgery, Harvard Medical School

    Panelists

    Tatsuo Kawai, MD, PhD

    Director of the Legorreta Center for Clinical Transplantation Tolerance,

    A.Benedict Cosimi Chair in Transplant Surgery, Massachusetts General Hospital;

    Professor of Surgery, Harvard Medical School

    Richard Pierson III, MD

    Scientific Director, Center for Transplantation Sciences, Massachusetts General Hospital;

    Professor of Surgery, Harvard Medical School

    Leonardo Riella, MD, PhD

    Medical Director of Kidney Transplantation, Massachusetts General Hospital;

    Harold and Ellen Danser Endowed Chair in Transplantation, Harvard Medical School

Concurrent Events

  • 12:00 PM – 12:45 PM

    Future of Cancer Care

    Moderator

    Alec Stranahan, PhD

    SMid-Cap Biotech Analyst, BofA Global Research

    Panelists

    Gerard Doherty, MD

    Surgeon-in-Chief, Mass General Brigham Cancer;

    Surgeon-in-Chief, Brigham and Women’s Hospital;

    Moseley Professor of Surgery, Harvard Medical School

    Daphne Haas-Kogan, MD

    Chief, Enterprise Radiation Oncology, Mass General Brigham;

    Professor, Harvard Medical School

    Benjamin Kann, MD

    Assistant Professor, Brigham and Women’s Hospital & Harvard Medical School

    David Ryan, MD

    Physician-in-Chief, Mass General Brigham Cancer;

    Professor of Medicine, Harvard Medical School

  • 12:00 PM – 12:45 PM

    Generative AI Enabled Care Paths

    Moderators

    Adam Ron

    Health Care Facilities and Managed Care Analyst, BofA Global Research

    Marc Succi, MD

    Executive Director, Mass General Brigham MESH Incubator;

    Associate Chair of Innovation & Commercialization, Mass General Brigham Radiology;

    Assistant Professor, Harvard Medical School

    Panelists

    Christopher Longhurst, MD

    Chief Medical & Digital Officer, UC San Diego Health

    Rebecca Mishuris, MD

    Chief Medical Information Officer, Mass General Brigham;

    Member of the Faculty, Harvard Medical School

    Shiv Rao, MD

    CEO & Founder, Abridge

    Alkesh Shah

    Head of US Equity Software Research, BofA Global Research

  • 12:00 PM – 12:45 PM

    Transforming Care in a Resource Limited Era

    Moderator

    Niyum Gandhi

    CFO & Treasurer, Mass General Brigham

    Panelists

    Fritz François, MD

    Executive Vice President and Vice Dean, Chief of Hospital Operations, NYU Langone Health

    Susan Huang, MD

    EVP, Chief Executive, Providence Clinical Network, Providence Southern CA

    Ron Walls, MD

    Chief Operating Officer, Mass General Brigham;

    Neskey Family Professor of Emergency Medicine, Harvard Medical School

  • 12:00 PM – 12:45 PM

    Cardiovascular Pipeline Renewal

    Moderators

    Jason Gerberry

    Specialty Pharma and SMid-Cap Biotech Analyst, BofA Global Research

    Calum MacRae, MD, PhD

    Vice Chair for Scientific Innovation, Department of Medicine, Brigham and Women’s Hospital;

    Professor of Medicine, Harvard Medical School

    Panelists

    Lotte Bjerre Knudsen, DMSc

    Chief Scientific Advisor, Novo Nordisk

    David Grayzel, MD

    Partner, Atlas Venture

    Christoph Westphal, MD, PhD

    General Partner, Longwood Fund

    Deborah Wexler, MD

    Chief, Diabetes Unit, Massachusetts General Hospital;

    Associate Professor of Medicine, Harvard Medical School

  • 12:45 PM – 1:00 PM

  • 1:00 PM – 1:20 PM

    Picasso Ballroom

    Opening Remarks

    Introducer

    Miceal Chamberlain

    President of Massachusetts, Bank of America

    Opening Remarks

    Maura Healey

    Governor of the Commonwealth of Massachusetts

  • 1:20 PM – 2:00 PM

    Picasso Ballroom

    Healthcare Innovation and Regional Competitiveness

    Panelists

    John Fish

    Chairman & CEO, Suffolk

    Reshma Kewalramani, MD

    CEO & President, Vertex Pharmaceuticals

    Jonathan Kraft

    President, The Kraft Group;

    Board Chair, Massachusetts General Hospital

  • 2:05 PM – 2:30 PM

    Picasso Ballroom

    Fireside

    Fireside Chat

    Moderators

    Tazeen Ahmad

    SMid-Cap Biotech Analyst, BofA Global Research

    Roger Hajjar, MD

    Director, Gene & Cell Therapy Institute, Mass General Brigham

    Panelist

    Reshma Kewalramani, MD

    CEO & President, Vertex Pharmaceuticals

  • 2:35 PM – 3:10 PM

    Picasso Ballroom

    Delivering Care: New Tools, Evolving Challenges, Bold Aspirations

    Moderator

    Andrew Bressler

    Washington Healthcare Policy Analyst, BofA Global Research

    Panelists

    Rod Hochman, MD

    President & CEO, Providence

    Anne Klibanski, MD

    President & CEO, Mass General Brigham;

    Laurie Carrol Guthart Professor of Medicine, Harvard Medical School

    Kevin Mahoney

    CEO, University of Pennsylvania Health System

  • 3:10 PM – 3:35 PM

    Picasso Ballroom

    Fireside

    Fireside Chat

    Moderators

    Caroline Sokol, MD, PhD

    Assistant Physician, Massachusetts General Hospital;

    Assistant Professor, Harvard Medical School

    Charlie Yang, PhD

    Large/SMid-Cap Biotech and Major Pharma Analyst, BofA Global Research

    Panelist

    Mark McKenna

    Chairman & CEO, Mirador Therapeutics

3:40 PM – 4:05 PM

Picasso Ballroom

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Fireside

Fireside Chat

Moderators

Jason Gerberry

Specialty Pharma and SMid-Cap Biotech Analyst, BofA Global Research

Allan Goldstein, MD

Chief of Pediatric Surgery, Massachusetts General Hospital;

Surgeon-in-Chief, Mass General for Children;

Marshall K. Bartlett Professor of Surgery, Harvard Medical School

Panelist

Christophe Weber, President & CEO, Takeda

  • pipeline is very diverse at the R&D center in Boston

Phase III:

  • TAK-279 Psorisis
  • Neurocrine’s Takeda-Partnered Drug Candidate Aces Phase II Depression Study

The Markets for Takeda

  • US market is 40% of revenue, It is a difficult market but still the most important for Phama in the World
  • Japan is 8%
  • Growth by acquisitions and internal development like above, two Phase III drugs

Price control and policies:

  • negotiation
  • price war create tension

Team:

Public company traded in NYSE

  • Management team has 10 nationalities – Global company
  • AI is adopted as a digital companion

Recruiting Patients for Clinical Trial:

  • Very difficult

M&A

  • After acquisition of Shire – not many other opportunities are left

4:05 PM – 4:40 PM

Picasso Ballroom

The Innovation Gap: A Review of the Future of Viral Vector Manufacturing and the Delivery of Genetic Medicines

Moderators

Elizabeth Henske, MD, Director, Center for LAM Research and Clinical Care, Brigham and Women’s Hospital; Professor of Medicine, Harvard Medical School

Alec Stranahan, PhD, SMid-Cap Biotech Analyst, BofA Global Research

Panelists

Peter Anastasiou, CEO, Capsida Biotherapeutics

  • Capsid technology for Liver disease, Parkinson’s
  • AV and CNS crossing BBB
  • One capsid for one disease
  • manufacture caspids
  • Challenges:  manufacturable after screening
  • IV delivery – brain disorder, blood flow would bring therapeutics to all brain tissue consistently vs localized
  • Partnership with Eli Lilly and with Crisper technologies with Abbvie

Steve Favaloro, Chairman & CEO, Genezen

  • 200 persons Team manufacture
  • Partnerships: synthetic plasma

Alexandria Forbes, PhD, CEO, MeiraGTx

  • Optimize promoters, control transcription expression by injection or by pill, control translation
  • improving potency of gene therapies capsule technology
  • cost hundred of $ not thousand of $
  • ALL manufacturing in house
  • 9 years of data can help to narrow down the parameters
  • time frame is shortened
  • company established 9 years ago
  • apply DNA expression – invented a technology
  • splicing control mRNA
  • control cell lines
  • give an injection or a pill and control antibodies, glucagon
  • control dosing for efficatious therapeutics
  • Potency
  • Ribozon is a delivery system
  • Partnership with J&J –

Fraser Wright, PhD, Chief Gene Therapy Officer, Kriya Therapeutics

  • manufacturing – changing in capsule design
  • manufacture viruses
  • cost of manufacturing – efficiency matters a lot
  • delivery of the gene in the tissue
  • Partnerships: basic vs applied Quality from research to manufacturing

4:45 PM – 5:20 PM

Picasso Ballroom

A Deep Dive on Genetic Modalities for Rare Disease: Genetic Medicines Are Here

Moderator

Tazeen Ahmad, SMid-Cap Biotech Analyst, BofA Global Research

  • Treat once or repeat therapy?

Patricia Musolino, MD, PhD, MGH

 

Panelists

Faraz Ali, Tenaya Therpeutics

  • genetic therapy for a genetic mutation – NOVEL approach
  • 400 mutation related to cardiomyopathy
  • 2018 – gene therapy was an innovation
  • genetic medicine Cardiology introducing opportunities wiht validation that did not exist
  • find novel targets Partnerships are a must to have
  • Viral therapies vs gene therapy

Lucas Harrington, PhD, Co-Founder & CSO, Mammoth Biosciences

  • How to turm Genome 2012 to therapy?
  • targeting: Taking risk Patient interaction with treatment
  • variation between Rare diseases some are very small some are not small – incentive to investors
  • The field will grow fast

Raju Prasad, PhD, Chief Financial Officer, CRISPR Therapeutics

  • various indications
  • FDA Approval
  • Gene editing technology for rare diseases
  • LPA for RNA therapy
  • incentive to investors
  • Important for investor to understand the siize of the market, CRISPR can be a technology for a large market size
  • Sickle cell disease – market is large and therapy can be made affordable

 

Sandi See Tai, MD, Chief Development Officer, Lexeo Therapeutics

  • cardiomyopathy
  • protective gene
  • Early genetic testing
  • Educating patients

5:20 PM – 6:30 PM

Picasso Terrace and Harborside Lawns 1 & 2

Tuesday, September 24, 2024

8:00 AM – 8:55 AM

Picasso Ballroom

The Transforming World

Introducer

Liz Everett Krisberg, Head of Bank of America Institute

  • Record attendance this year
  • Introduction to Haim

Panelist

Haim Israel

Head of Global Thematic Investing Research, BofA Global Research

  • Concept of the Future and for the Future: Short-term and long-term
  • Humanity achievements in Ten Year: Data, Processing power and BRAIN – Long-term becomes Short-term – Last 10 years: 2012, 2014 solar system, 2015 medicine, 2019 blackhole, 2023 core of sun – star was created hotter than core sun
  • 2022, 2024 – galaxy picture of the universe
  • Volume of data created every month in terrabyts every 18 month data is duplicating itself.
  • Olny 1% is used – imagine 2% or 3%
  • Processing power since Apollo 11 [one trillion] – getting cheaper – cost for calculation went down 16,000 fold since 1995
  • AMMOUNT of DATA goes up and Cost of COMPUTATION goes down – price per giga byte
  • Projections for the next 100 years
  • Negative for people and Negative for Companies who are concerned with quarterly financial data
  • Companies: Walmart, Alphabet, Home Depot – DATA larger that COuntries
  • Living in defining moment: started by iPhone revolution and 2023 by AI revolution – 6x outpaced Moore’s Law by GPT by 3000x
  • 18 months into AI revolution – GPT in use
  • The next 10 years:
  1. Aging population
  2. 2024 – birth rate low in US, Japan, CHina, S. Korea – Pension system will decline in size
  3. 2.2 millions new material were created by DeepMind at Alphabet by simulation of AI on molecule
  4. Microsoft in 80 hours identified 18 materials winners for Batteries using AI from 32 million material candidates
  5. AI- weather calculations in minutes 1,000x faster, cheaper and more accurate
  6. 2025 – GPT-6 AI surpass Human Brain
  7. China is a big player in AI
  8. Cyber CRIME is the 3rd largest economy in the World. Hackers are using ChatGPT to create fake pictures leading to ZERO privacy
  • PRIVACY: Deepfakes up 62x, social media
  • 2024 – Global Grid – needs much more energy because AI consumes so much energy
  • Metals shortages: Nickel, Copper,
  • Scarcity of water for 2/3 of the planet
  • data centers consume water more than Japan
  • 2025 – Genomics Data sequencing bigger that X.com or Youtube
  • 2027 – Peak oil demand: needed to be scalable, cheaper 25%
  • 2028 – 5G networks reaches full capacity, 6G will be needed
  • 2029 – 25x more satellites in Orbit than today
  • 2029 – Personalized AI medicines and treatments will manipulate death and revive LONGEVITY – AI will generate drugs and all treatments
  • 2030Generative AI:  re-skill 1 Billion people
  • 2035 – Fusion energy, known technology since the atomic bomb, how to keep it stable in plasma state of material – not yet achieved, it is clean, cheap: to Power the World – equivalent of 11 barrels of oil
  • Large cities: Cable diameter 17cm wide to power a large city
  • AI will change scarcity into abundance
  • 2037 – Artifitial SUPER Intelligence – AI to outsmart Life
  • Quantum computer – Consortium of NASA and other governmental agencies and Google on quantum computer design
  • 2024 the most interesting year in human history

 

Concurrent Events

  • 9:00 AM – 9:45 AM

    Current and Future States of Immunology

    Moderators

    Caroline Sokol, MD, PhD, Assistant Physician, Massachusetts General Hospital;, Assistant Professor, Harvard Medical School

    Alec Stranahan, PhD, SMid-Cap Biotech Analyst, BofA Global Research

    Panelists

    Dong Feng Chen, MD, PhD, Associate Scientist, Massachusetts Eye and Ear;, Associate Professor, Harvard Medical School

    Steven Grinspoon, MD, Chief, Metabolism Unit, Massachusetts General Hospital; Professor of Medicine, Harvard Medical School

    Alexandra-Chloé Villani, PhD, Investigator, Massachusetts General Hospital; Assistant Professor, Harvard Medical School

  • 9:00 AM – 9:45 AM

    Therapeutic Psychedelics – Opportunities and Impact

    Moderators

    Maurizio Fava, MD

    Chair, Department of Psychiatry, Massachusetts General Hospital;

    Slater Family Professor of Psychiatry, Harvard Medical School

    Jason Gerberry

    Specialty Pharma and SMid-Cap Biotech Analyst, BofA Global Research

    Kerry Ressler, MD, PhD

    Chief Scientific Officer, McLean Hospital;

    Professor of Psychiatry, Harvard Medical School

    Panelists

    Cristina Cusin, MD

    Director, MGH Ketamine Clinic and Psychiatrist, Depression Clinical and Research Program, Massachusetts General Hospital;

    Associate Professor in Psychiatry, Harvard Medical School

    Daniel Karlin, MD

    Chief Medical Officer, MindMed

    John Krystal, MD

    Chair, Department of Psychiatry, Yale School of Medicine

    Jennifer Warner-Schmidt, PhD

    Vice President, Scientific Affairs, Transcend Therapeutics

  • 9:00 AM – 9:45 AM

    Innovations Advancing Community Health Equity

    Moderators

    Allen Lutz

    Health Care Services Analyst, BofA Global Research

    Elsie Taveras, MD

    Chief Community Health & Health Equity Officer, Mass General Brigham;

    Conrad Taff Endowed Chair and Professor of Pediatrics, Harvard Medical School

    Panelists

    Rebecca Mishuris, MD

    Chief Medical Information Officer, Mass General Brigham;

    Member of the Faculty, Harvard Medical School

    Claire-Cecile Pierre, MD

    Vice President, Community Health Programs, Mass General Brigham;

    Instructor in Medicine, Harvard Medical School

    Jorge Rodriguez, MD

    Clinician-investigator, Brigham and Women’s Hospital;

    Assistant Professor, Harvard Medical School

    Prabhjot Singh, MD, PhD

    Senior Advisor, Strategic Initiatives Peterson Health Technology Institute

  • 9:00 AM – 9:45 AM

    Earliest Detection

    Moderators

    James Brink, MD

    Enterprise Chief, Radiology, Mass General Brigham;

    Juan M. Taveras Professor of Radiology, Harvard Medical School

    David Louis, MD

    Enterprise Chief, Pathology, Mass General Brigham

    Benjamin Castleman Professor of Pathology, Harvard Medical School

    Jason Zemansky, PhD

    SMid-Cap Biotech Analyst, BofA Global Research

    Panelists

    Jasmeer Chhatwal, MD, PhD

    Associate Neurologist, Massachusetts General Hospital;

    Associate Professor of Neurology, Harvard Medical School

    Pradeep Natarajan, MD

    Director of Preventive Cardiology, Paul & Phyllis Fireman Endowed Chair in Vascular Medicine, Massachusetts General Hospital;

    Associate Professor of Medicine, Harvard Medical School

    Yakeel Quiroz, PhD

    Director, Familial Dementia Neuroimaging Lab and Director, Multicultural Alzheimer’s Prevention Program, Massachusetts General Hospital;

    Paul B. and Sandra M. Edgerley MGH Research Scholar;

    Associate Professor, Harvard Medical School

    Heidi Rehm, PhD

    Chief Genomics Officer, Massachusetts General Hospital;

    Professor of Pathology, Harvard Medical School

  • 9:00 AM – 9:45 AM

    Women’s Health Technology Revolution

    Moderators

    Tazeen Ahmad

    SMid-Cap Biotech Analyst, BofA Global Research

    Hadine Joffe, MD

    Executive Director of the Connors Center for Women’s Health and Gender Biology;

    Interim Chair, Department of Psychiatry, Brigham and Women’s Hospital;

    Paula A. Johnson Professor of Psychiatry in the Field of Women’s Health, Harvard Medical School

    Panelists

    Keith Isaacson, MD

    Director of Minimally Invasive Gynecologic Surgery and Infertility, Newton Wellesley Hospital;

    Associate Professor of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School

    Nawal Nour, MD

    Chair, Department of Obstetrics and Gynecology, Brigham and Women’s Hospital;

    Associate Professor, Kate Macy Ladd Professorship, Harvard Medical School

    Kaveeta Vasisht, MD, PharmD

    Associate Commissioner, Women’s Health, U.S. Food and Drug Administration

    Alice Zheng, MD

    Principal, RH Capital

9:50 AM – 10:15 AM

Picasso Ballroom

Fireside

Fireside Chat

Moderator

David Brown, MD, President, Academic Medical Centers, Mass General Brigham; Mass General Trustees Professor of Emergency Medicine, Harvard Medical School

  • Hoe do you balance Private medicine with Public not for profit HealthCare
  • Healthcare delivery system can achieve that much in Human health
  • Resources for Equity: housing and services: Capacity and COst
  • Evolution of care close to home catalyst of the Pandemic – How government think about the right patient for the right care level
  • MGB 40-60 In-patients at Home – Largest Program in the State  – product needs to scale across all population though some do not have food security at home

Panelist

Kate Walsh, Secretary of Health and Human Services, State of Massachusetts

  • Stuart Bankrupcy – pstioents and providers involvement – structure challenges
  • Race and ethnicity – disparities, access and equity
  • Identify the challenge for Race and ethnicity
  • Focus to identify resources
  • Medicare & Medicaid – Human needs equity involve housing, food and home care – Public and Private sector cooperation
  • Pay for Performance
  • MA vs NYC – resources for welcoming new populations to the State of MA
  • Help finding Housing vs Shelter people
  • MA is the only State in the Union that is a Shelter State
  • People in our COuntry LEGALLY are in and out of shelters, new arrivals of skilled labor – temporary assistance to get jobs that we can’t find people to fill: CNA as example
  • MA has a community of shelters and medical center in the communities
  • Services for people that are at risk due to past life in home countries
  • Support for kids that do not speak English
  • Care and location: Keep care at home or SNF at home or in the community
  • Low income person at Home Hospital vs at MGB ?
  • Autist kids becoming Adult – how to care for ?

 

10:15 AM – 10:40 AM

Picasso Ballroom

Fireside

Fireside Chat

Moderators

Alec Stranahan, PhD, SMid-Cap Biotech Analyst, BofA Global Research

Teresa Gomez-Isla, MD, PhD, MGH, Neurology, Memory division

  • Altzheimer’s biomarkers
  • Clinical trials lessons on drug benefits

Panelist

David Hyman, MD, Chief Medical Officer, Eli Lilly and Company

  • Cardio-metabolic – medicines redefining disease by medicines benefit to patients
  • Investment in manufacturing medicines for Obesity, demand continue to expand
  • Oral small molecule and scaling focus on Sleep apnea, half of the population have metabolic disease and heart failure
  • Extension Program with sustained weigh loss in pre-diabetes progressing into maintained weigh loss
  • Invest in R&D in the cardio-metabolic
  • Listed to community feedback on experience how the drugs in AD affected patients in the Community – learning about challenges in delivery innovation in AD – irreversible neurodegenerative diseases – prevent not to loose the patients entirely – brain function
  • Targeted therapies, genetic therapies
  • Past life Oncologist – delivered innovations into Cancer patients – genetic medicines
  • AD medicines are not accessible even to people of means, Drug delivery using PET spinal injections
  • Ten years horizons at Eli Lilly is common
  • Obligation to provide scientific evidence from clinical trials
  • Inventory of patients qualification to participate in Clinical trials
  • Oncology: Interactions in biologics, cell therapies, conjucate compounds
  • Renewal of Targeting antigens
  • In Oncology: Proportions of patients get long term disease control by molecules developed in Academic Centers.
  • Eli Lilly acquired a BioPharma with manufacturing capabilities
  • Innovations are core vs discount cash-flow, strategy is to look at the science due to capacity to develop innovations

10:40 AM – 11:20 AM

Picasso Ballroom

Disruptors

The Disruptors: Metabolic Power…Need It…Want it

Moderator

Alec Stranahan, PhD, SMid-Cap Biotech Analyst, BofA Global Research

Caroline Apovian, MD, MGH, HMS

  • Last ten years, from metabolic lessons of Bariatric patients
  • Treat obesity before surgery
  • product composition
  • multidisciplinary approach to obesity needs to be like in Oncology – multiple dsciplines
  • Bariatric and weigh regain like stent stenosis after surgery
  • Obesity dysfunction inflammation Gut-Brain transfer of hormones from the gut do not reach the brain to carb hunger socieaty is not signaled in the Brain and eating continued to mitigate hunger
  • Insurance must cover
  • Obesity Medicine – training 25 new practitioners to treat Obesity – Standards of Care, life style change
  • Primary care providers do not have resources to treat Life style component of
  • To reduce mortality by 20% by Bariatric surgery – No reduce of mortality by stenting – THAT I DISAGREE with

 

Panelists

David Hyman, MD, Chief Medical Officer, Eli Lilly and Company

  • non-peptide agonist, bariatric level for obesity
  • peptide injecting device
  • hormones and peptids activan inhibitor
  • hundred of million of people – scaling up
  • Adolescence with obesity will develop CVD, NASH
  • Epidemic of obesity the medicines are combating the epidemic
  • Vials, differential pricing, orals vs injectables
  • Productivity of work force, coverage by employers health insurance vs Government to handle coverage
  • 10 additional drug

Xiayang Qiu, PhD, CEO, Regor Therapeutics

  • six years ago, great opportunity peptide and biologics for lifetime disease of obesity
  • cardiovascular favorably = affected by reduction in weigh
  • Medicines that works start early at age 35

Harith Rajagopalan, MD, PhD, CEO & Co-Founder, Fractyl Health

  • Diet & Life Style
  • Eli Lilly and Novo Nordik – have great drugs
  • Patients stop using them before they see the benefit
  • durable long term of mentainance long-tern to stay on the drug
  • Past life coronary cardiologist: PCI vs surgery choice of care angioplasty vs open heart surgery
  • Bariatric surgery vs great medicines
  • may be angioplasty for Bariatric patients
  • Obesity is different than CVD
  • BC-BS coverage of obesity drugs because weight is gained back vs Statins – continual use control cholestrol
  • maintenance drugs in the field of Obesity are needed
  • cost of drugs will come down
  • more evidence on obesity drugs will affect Formulary

 

11:20 AM – 12:00 PM

Picasso Ballroom

The Innovation Gap: The Broader Impact of Metabolic Drugs on Related Diseases

Moderator

Jason Zemansky, PhD, SMid-Cap Biotech Analyst, BofA Global Research

Patrick Ellinor, MD, PhD, MGH, HMS

Panelists

Craig Basson, MD, PhD, Chief Medical Officer, Bitterroot Bio

  • 17,000 patients obese no DM
  • prior CVD followed 3 yrs of treatment 6% mortality during the Trial
  • Death from CVD endpoint
  • weight at joining the trial, loss during the trial, benefir from the drug’
  • improve CVD not weigh loss
  • mechanism of Inflammation – drug, reduced atherosclerosis and reduced plaque and cytokins and inflammation improve CVD status
  • combination of life style and drugs GI axis systemic
  • cardiac artery disease: cholesterol, inhibit inflammatory signals plaque build on top of itself – approaches to remove debris macrophages in the plaque for artherosclerosis mechanism as CVD risk

Joshua Cohen, Co-CEO, Amylyx Pharmaceuticals

  • Bariatric surgery lower obesity
  • genetics, eating habits,
  • GLP-1 agonist developed

Punit Dhillon, CEO, Skye Bioscience

  • Phase II study combination therapy CVD and Obesity
  • optimize body composition – more productive on the body periphery
  • subtypes metabolic gains
  • Pharmacotherapy for obesity: mechanisms complementary life style change is a must have for long-term benefits
  • weight loss as a start before obesity treatment
  • co-morbidities of obesity

Justin Klee, Co-CEO, Amylyx Pharmaceuticals

  • Parkinson’s CNS peripheral Brain access therapies
  • revolution in metabolic disease treatment options, more studies for pathways to target the right patients for the right treatment
  • GLP-1 is energy regulator, Hypoglycemia is very dangerous

Rohan Palekar, CEO, 89bio

  • applications to obesity – data support
  • bariatric surgery intervention is not enough, NASH will not be impacted only by the surgery
  • NASH is a disease taking 25 years to develop
  • risk of fibrosis to set in Cirrhosis which is not curable

 

Concurrent Events

  • 12:15 PM – 1:00 PM

    ARPA-H: Opening New Frontiers in Health Innovations

    Panel of 5

    Glioblastoma Treatment Reinvented

    Moderators

    E. Antonio Chiocca, MD, PhD

    Chair, Department of Neurosurgery, Brigham and Women’s Hospital;

    Harvey W. Cushing Professor of Neurosurgery, Harvard Medical School

    Charlie Yang, PhD

    Large/SMid-Cap Biotech and Major Pharma Analyst, BofA Global Research

    Panelists

    Natalie Artzi, PhD

    Associate Professor of Medicine, Brigham and Women’s Hospital & Harvard Medical School

    Bryan Choi, MD, PhD

    Associate Director, Center for Brain Tumor Immunology and Immunotherapy, Massachusetts General Hospital;

    Assistant Professor of Neurosurgery, Harvard Medical School

    Alexandra Golby, MD

    Neurosurgeon;

    Director of Image-guided Neurosurgery, Brigham and Women’s Hospital;

    Professor of Neurosurgery, Professor of Radiology, Harvard Medical School

  • 12:15 PM – 1:00 PM

    Healthcare Corporate Venture

    Moderator

    Roger Kitterman

    Senior Vice President, Ventures and Business Development & Licensing, Mass General Brigham

    Managing Partner, Mass General Brigham Ventures

    Panelists

    Rahul Ballal, PhD

    CEO, Mediar Therapeutics

    Tim Luker, PhD

    VP, Ventures & West Coast Head, Eli Lilly

    James Mawson

    CEO, Global Corporate Venturing

  • 12:15 PM – 1:00 PM

    Inflammation Pathways

    Moderators

    Tazeen Ahmad

    SMid-Cap Biotech Analyst, BofA Global Research

    Katherine Liao, MD

    Associate Physician, Department of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital;

    Associate Professor of Medicine and Biomedical Informatics, Harvard Medical School

    Panelists

    Jessica Allegretti, MD

    Director, Crohn’s and Colitis Center, Brigham and Women’s Hospital;

    Associate Professor of Medicine, Harvard Medical School

    Andrew Luster, MD, PhD

    Chief, Division of Rheumatology, Allergy and Immunology;

    Director, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital;

    Persis, Cyrus and Marlow B. Harrison Professor of Medicine, Harvard Medical School

    Thorsten Mempel, MD, PhD

    Associate Director, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital;

    Professor of Medicine, Harvard Medical School

  • 12:15 PM – 1:00 PM

    Hospital at Home

    Moderators

    Joanna Gajuk

    Health Care Facilities and Managed Care Analyst, BofA Global Research

    Heather O’Sullivan, MS, RN, AGNP

    President, Mass General Brigham Healthcare at Home

    Panelists

    O’Neil Britton, MD

    Chief Integration Officer & Executive Vice President, Mass General Brigham

    Jatin Dave, MD

    Chief Medical Officer, MassHealth;

    Director of Clinical Affairs, UMass Chan Medical School

    Chemu Lang’at

    Chief Operating Officer, Best Buy Health

1:05 PM – 1:45 PM

Picasso Ballroom

Pioneering Digital Transformation

Moderator

Liz Kwo, MD, Chief Commercial Officer, Everly Health

  • Infrastructure
  • AI used for

Panelists

Anna Åsberg, Vice President, AstraZeneca Pharmaceuticals

  • Massive data bases organize
  •  AI to augment intelligence inside the data

Tyler Bryson, Corporate Vice President, US Health & Public Sector Industries, Microsoft Corporation

  • Do we have platforms to serve new problem
  • Regulatory changes require visiting use cases
  • Pharma has the research data, providers have EMR – Microsoft builds new models using that data
  • Tumor imaging data was processed and new pattern recognition done on data of these tumors. New patterns are now a subject for research, just identified inside the data
  • Trust in Healthcare
  • NYC and Microsoft developed a System for small businesses to access city resources
  • Works with Academic institutions: Programs at Harvard and Princeton to train students by Microsoft employees on MIcrosoft AI technologies that as they graduate there will be trained new AI-trained employees
  • collaborations

Aditya Bhasin, BofA

  • AI in Banking: Bias, security
  • AI virtual system analytics to provide insight for scaling

Jane Moran, MGH

  • Network, Data structure needs updates
  • technology to help clinicians
  • care team to work with Generative AI to assist in e-mail reading and problem solving
  • Healthcare equity – avoid Bias
  • AI is not an answer to every problem
  • innovate at scale: using Epic and Microsoft
  • Clinical data structure for LLM, AI to renovate administrative processes inside MGH
  • Data structure for transperancy
  • Digital Rounds like Medical ROunds audit problems
  • equity in data

1:45 PM – 2:25 PM

Picasso Ballroom

Capital Formation: Putting Money to Work – State of Affairs in Capital Markets

Moderators

John Bishai, PhD, BofA

  • valuations went down

Brendan Singleton, Healthcare Equity Capital Markets, BofA Securities

  • what impact Capital flow

Emma Somers-Roy, Chief Investment Officer, Mass General Brigham

Panelists

Chris Garabedian, Chairman & CEO, Xontogeny; Venture Portfolio Manager, Perceptive Advisors

  • Valuations done with comparables for IPO
  • Not quick to invest in companies, responsible behavior
  • Private rounds, Biotech and Pharma strategic partners
  • M&A stable requires are exciting valuation
  • foundations, institutional investors – level of interest is related to valuations number of years to exit
  • Peak sale, Public markets different than Private markets
  • Obesity is a crowd space, diferentiation is important
  • Exit tow ways: year for IPO natural acquirer – Who is he??
  • Cancer was a dominant now CNS, Cardio-metabolic, ophthalmology
  • size of market – Cancer was attractive, less in 2024
  • Early venture investor: 50-100MM valuation to 2Bil
  • CMS has discounting since profits are been realize at present time
  • Patents`
  • Presidential election
  • investors scarce pushed fewer mega rounds 100MM financing requires early clinical data
  • Hedge fund very conservative with valuations
  • Downsize in Biotech is over

Arjun Goyal, MD, Vida Ventures

  • Investment in private markets
  • 2019-2021 – IPOs on narratives and proof of concept, only only, no financials
  • M&A or Partnering – financial risk clinical data point
  • validation of team success
  • size of market is very important
  • Innovation matters always in Pharma, prospects for Biotech very bright
  • what is HOT in a moment
  • combination therapies
  • Life cycle: compound right gene, financing history, fundamentals
  • calibration of market valuations

 

2:25 PM – 2:50 PM

Picasso Ballroom

Fireside

Lessons Learned Shaping New Horizons: Visionary Change Agent Perspectives

Moderator

Yvonne Hao, Secretary of Economic Development, Commonwealth of Massachusetts

  • accelerate AI adoption by nurses, How do you do that??
  • Public private partnerships
  • If you have a blank slate – do it differently

Great impact of Cleveland Clinic

Panelists

Delos “Toby” Cosgrove, MD, Executive Advisor; former CEO & President, Cleveland Clinic

  • Housing, education, research beyond healthcare
  • Reduce cost in healthcare, call centers by AI: equipment to measure BP every 4 hours
  • Technology is approved 13 years to become standard of care
  • COST in healthcare requires SALVATION
  • mistakes by leadership
  • Regulators have their share in current situation of Healthcare
  •  Leadership in Health care must change

Marc Harrison, MD, Co-founder & CEO, Health Assurance Transformation Corp. (HATCo)

  • collaborate with competitors
  • AI is a tool not a solution
  • Streamline processes to reduce costs
  • Government should not solve the Healthcare problem
  • Residents are victims of leaders mistakes
  • Only healthcare industry sees the medical records of all the population
  • gene therapy, innovations to change healthcare and get financial solvency

2:50 PM – 3:15 PM

Picasso Ballroom

Fireside

Fireside Chat

Moderators

Andrew Bressler, Washington Healthcare Policy Analyst, BofA Global Research

  • What is coming up in the next two years
  • Are you growing and Hiring?

Yvonne Hao, Secretary of Economic Development, Commonwealth of Massachusetts

  • AI – what is the potential for Healthcare
  • MA to work with ARPA-H

Panelist

Renee Wegrzyn, PhD, Director, Advanced Research Projects Agency for Health – A Federal Governmental Agency

  • ARPA-H Model was introduce under the Advanced Research Projects Agency for Health
  • Hired 21 Program Managers to manage Health initiatives in research
  • Health is not a partizan affair
  • Bring young innovators, mantored by experiences healthcare professionals
  • cellular therapeutics is an example selected to advanced the field
  • Data driven – looking at +100 project approved by government agency
  • Governtment, Academia, Private sector – SOLICITATIONS for solving a research problem
  • Technical merit in judging applications
  • Value-baced pricing – data to influence policy FDA, NIH collaboration
  • FDA to finance projects spending
  • Pediatrics
  • President announced a program for ARPA-H to work on
  • Investors are welcome to review proof of concepts of ARPA-H
  • Return on Investment for all Americans’ Tax payers money
  • Yes, growing and hiring. $1.5 milion budget

 

 

3:15 PM – 3:20 PM

First Look

3:20 PM – 3:35 PM

Selector of Winner: Doug Marshall & Paul Anderson, MD, PhD

 

3:35 PM – 4:15 PM

Picasso Ballroom

Disruptors

The Disruptors: The Biologic Revolution in Radiotherapies

Moderator

John Bishai, PhD, Global Healthcare Investment Banking, BofA Securities

Umar Mahmood, MD, PhD, MGH, HMS

Panelists

Amos Hedt, Chief Business Strategy Officer, Perspective Therapeutics

  • imaging used to deliver the therapeutics before the drug touch the patient to calculate toxicity
  • PL-1 combined with radiotherapy synergistics results
  • immunogenic combination therapy, in presence of these agents, immune response reaction in the immune cells

Matthew Roden, PhD, President & CEO, Aktis Oncology

  • Conjugates – delivery direct to tumors
  • Opportunity two targets: (1) SSTA2 marker (2) xx
  • WHen agent inside the tumor, shrinkage and no emergence of cell nascent 
  •  optimization design
  • Treatment break for patients and families

Philip Kantoff, MD, Co-Founder & CEO, Convergent Therapeutics

  • Radio-pharmeceutics : 10 days half-life carrier not a target for small molecules Data on 120 patient, namo robust response synergy of antibody and molecule
  • image alphas
  • durable responses

Matt Vincent, PhD, AdvanCell Isotopes

  • ROS species generated in the tumor
  • peptides, protein binders
  • paradigm shift in delivery of oncology therapeutics directly to tumors

Lena Janes, PhD, Abdera Therapeutics

  • isotope will deliver the payload without damaging the DNA and healthy tissue
  • target different types of tumors, different half-life
  • Radiation therapy using isotopes id one of two modalities: tumor in and tumor out approach
  • screen for patient for the translational therapy
  • Next generation of products will come, now it is the beginning of these agents

4:20 PM – 4:45 PM

Picasso Ballroom

Fireside

Fireside Chat

Moderator

Michael Ryskin, Life Science Tools & Diagnostics Analyst, BofA Global Research

  • Precision Medicine was it a paradigm shift??
  • Acquisition of manufacturing capabilities
  • research, manufacturinf line blurred
  • WHat excites you the most

Panelist

Marc Casper, Chairman, President & CEO, Thermo Fisher Scientific

  • Enabling Life sceinces, Pharmaceutical industries $1.5Billion internal investment annually
  • AI increasing knowledge
  • How is Precision Medicine applied? Sequencing in Cancer accelerated the Genomics information in use for 24 hours response of the sequence – adopted around the World.
  • at MGH lung cancers are treated with genomic sequencing
  • identification of the patients suitability for a targeted treatment
  • treatment during pregnacy at home vs hospitalization
  • History of company: Tools first: Mass spectrometry, one year for one sequence, protein identification and carrying to Mass spectrometry
  • Interactions need understanding acquiring electro spectrometry allowing analytical chemistry on proteins
  • Broad range of products: Clinical research to meet regulatory requirements entry into Reagents products.
  • Clinical Trials made effective by Thermo Scientific Products
  • Capabilities in registries, patient safety in psoriasis
  • Large role in experimental medicine drives efficiency in LABS
  • SIze of customers: small Biotech and large Pharma
  • Manufacture medicines: work with partnersbuilt by acquisitions small molecules,
  • 100 engagements research, supply chain making medicines available at sites
  • Role for AI at Thermo Scientific:
  1. Productivity – Cost effective for processes in use by 120,000 employees
  2. Super customer interaction perfected by interogations with internal manuals to provide answers quickly
  3. Improvement of products
  • Excitement Points: Responsiveness to COVID pandemic
  • New medicine development

4:50 PM – 5:30 PM

Picasso Ballroom

The Reemergence of ADCs, Precision Medicine, T-cell engagers, and Bispecifics: Oncology at Its Finest

 

Moderators

John Bishai, PhD, BofA

  • Approach to AI
  • Strategy regarding clinical trial design, vs molecule design

Justin Gainor, MD, MGH, HMS

  • How strategies are developed and then modified?
  • immune therapies work better open new paradeigm

Panelists

Moitreyee Chatterjee-Kishore, PhD, Head of Development, Immuno-Oncology and Cancer Cell Therapy, Astellas Pharma Inc.

  • cancer – first line of treatment vs 2nd and 3rd
  • Precision medicine more precise
  • mix and match immunotherapy and other modalities
  • small molecule early on
  • molecule formulation is science and art
  • Stratify the patient population early on
  • Help needed to design better trials
  • Research is key for molecule design

Niall Martin, PhD, CEO, Artios Pharma

  • peptide chemistry
  • molecule design had options several are applied
  • biomarker driven event in development cycle
  • strategy of biomarkers – lack structure
  • effect of combination therapy on survival?

Chris Varma, PhD, Co-founder, Chairman & CEO, Frontier Medicines

 

5:30 PM – 8:30 PM

South Lawn Tent

Attendee Reception and Dinner

Moderator

Anne Oxrider

Senior Vice President, Benefits Executive, Bank of America

Panelist

Deepak Chopra, MD

Founder, The Chopra Foundation

Wednesday, September 25, 2024

8:30 AM – 8:55 AM

Picasso Ballroom

Fireside

Fireside Chat

Moderators

David Ting, MD, Associate Clinical Director for Innovation, Mass General Cancer Center; Associate Professor of Medicine, Harvard Medical School

  • Innovation is the foundation of the future
  • Creative thinking vs one agent and one target
  • Openness is much appreciated

Jason Zemansky, PhD, SMid-Cap Biotech Analyst, BofA Global Research

  • On WSJ article on M&A in Biotech attributing decline in M&A of Biotech companies due to LACK of Innovations
  • Q from audience: organizational structure and innovation
  • Vision on leveraging Partnerships

Panelist

Tadaaki Taniguchi, MD, PhD, Chief Medical Officer, Astellas Pharma

  • Pharma and Biotech heavy betting on new medicines in Oncology
  • Astellas Pharma is different than other Pharma companies
  • We focus on Oncology and in combination therapies as a priority
  • Investment pay attention to Leadership priorities
  • One product vs BEST combination therapy for best treatment and outcomes
  • Innovations come from anywhere
  • ADCs: Target, payload emerged recently by a partnership
  • Collaborations: several pathways, several modalities, several combinations therapies
  • Partnership requires greater flexibility
  • Created Small flexible Labs to enable to innovate with Partners, “we can’t innovate alone”

9:00 AM – 9:40 AM

Picasso Ballroom

Disruptors

The Disruptors: The Role of Pathway Inhibition in Inflammation and Inflammatory Diseases

Moderators

Tazeen Ahmad, SMid-Cap Biotech Analyst, BofA Global Research

  • Are you using AI
  • Neuroinflammation

Cynthia Lemere, PhD, BWH, HMS

  • What systems are primarily impacted by the Immunes system
  • Drug delivery for inflammation huge area
  • Getting antibodies to the Brain
  • Precision medicine, genetics,specific person with specific immune disease

Panelists

Jo Viney, PhD, Cofounder, President & CEO, Seismic Therapeutic

  • Pandemics highlighted the impact of the immune system
  • Targeting cytokines in specific locations – hew approach
  • Modalities on hand: protein degradation mediation by bringing two cells together
  • AI is used for Patient stratification
  • AI to be used in Pathways involved in disease process to identify Biologics, PROTAC,
  • AI and ML for training models from interaction between proteins
  • ChatGPT to predict interactions among proteins
  • Immune disease and remission bust the immune system to improve quality of life of patient undergoing interventions
  • T-cell engaggers – in cases of refractory – great approach for boosting the immune system: removal of antibidies, recycling antibodies,
  • Two ends: Cell depletion vs Early detection
  • Therapy is every 6 months, cell depletion takes 3 months to come back.
  • Target immune system in the periphery,
  • Immune system in neurodegenerative diseases: Parkinson’s local modulation to penetrate neurological system
  • Markers to cross the BBB or not cross in neurological diseases
  • Immune disease is POLYGENIC multiple o=etiologies, mutation, genetics, which cell and which pathway to target a therapeutics: Biologics
  • Patient stratification is key for Precision Medicine at the cell level
  • T-cell, B-cell, Cytokines and antibodies mediated disease
  • ADGs degradation

9:45 AM – 10:10 AM

Picasso Ballroom

H. Jeffrey Wilkins, MD, Abcuro
  • Inflammation play a role in activating the immune system
  • zin the days of Medical School: inhibition of cytokines
  • Today: specificity to target cells for depletion
  • Specific biomarkers for response to therapies
  • cell types by mutations and physiology and causality in the inflammation area: we know why they have inflammation we need to learn interventions for inflammation
  • Asthma in the 40s as an inflammatory disease
  • assess treatment of inflammation
  • Neuro-inflammation – not well understood
  • What is the cause that drive the disease: understanding encephalitis?
NiranJana Nagarajan, PhD, MGB Ventures
  • Biology is the driver not AI
  • depletion of cells in a certain stage
  • Translation from disease to other diseases in the case of cell therapy potential – active area companies are trying solutions
  • Inflammation is a huge challenge to treat

 

Fireside

Fireside Chat

Moderators

Daniel Kuritzkes, MD, Chief, Division of Infectious Diseases, Brigham and Women’s Hospital; Harriet Ryan Albee Professor of Medicine, Harvard Medical School

  • Pathways in vaccine design
  • How to educate population on Vaccines
  • other approaches than vaccines

Alec Stranahan, PhD, SMid-Cap Biotech Analyst, BofA Global Research

  • Vaccine approval
  • Next generation vaccines

Panelist

Stéphane Bancel, CEO, Moderna

  • Vaccine design: long term vaccines weakens in aged population
  • data on role of AVV in Multiple Sclerosis
  • working on in the US vs France, Netherland in Europe different approaches
  • Vaccine for HIV
  • Vaccine was approved last year for children, pharmacies shortage
  • Season of FLu three times more vaccines in use
  • Employees run vaccine clinics on site
  • Vaccines not related to COVID
  • Misinformation from COVID vaccine
  • 5% of COVID hospitalized were on the booster
  • Combination vaccines for high risk populations
  • Healthcare providers need to be involved in Education, many do not have an interest in the education on vaccines
  • Local stories from Vaccine manufectures and developer to be used in education in the communities
  • Individual DNA cancer celll signature of the cancer  – data over time for development of vaccine to cancer many more tumor types are needed
  • Checkpoints in early disease
  • biopsy are too expensive
  • Side effect studies going on
  • mono-therapy vs immunotherapy costs involved
  • Naive virus to get into the Liver two diseases – cassets for sose management
  • Recombinant antibodies technology from the 70s
  • PD-1
  • COVID – was nto in the plan for development – design in silicon in two weeks – no change after this design
  • 10:10 AM – 10:20 AM

10:20 AM – 11:00 AM

Picasso Ballroom

The Innovation Gap: Understanding the Role of Cell Therapies in Autoimmune Disease

Moderator

Charlie Yang, PhD

Large/SMid-Cap Biotech and Major Pharma Analyst, BofA Global Research

  • TCM
  • CAR-T
  • advantages of each cell type

Angele Shen, MGB Innovations

  • CAR-T
  • What would be a quick breakthrough?

Panelists

Jeff Bluestone, PhD, CEO & President, Sonoma Biotherapeutics

  • Cell therapy for cell depletion elimination of B-cells like its role in Multiple Sclerosis
  • Working with regulatory T-cells
  • Population of cells to study: T-cells master regulator in multiple ways – produce metabolic factors, infection tone in activation of other cells
  • Biology of cell: RNA, DNA
  • TCR – target antigens in tissues they are in in immune suppression
  • FInding the right peptide bindes to a certain MAC
  • CAR-T – recornize the cells in the local milieu like in patients with RA as an autoimmune disease
  • Clinical models ascertain cell types involvement leading to clinical trial insights then to therapies on a decision tree
  • recent data on CAR-T immune response in allogeneic for potential use in neurodegenerative diseases
  • patients and companies over react on immune therapy: Patients and Science vs hype
  • next generation: POC,
  • Gene therapy specificities vs Cell therapies – each approach will develop a different drug
  • FDA and NIH has in 11/2023 a meeting on Regulation of Cell therapy on stability and their approach to immune disease where there are already several drugs
  • approvals challenges companies
  • Price, too expensive a treatment is cell therapy

Chad Cowan, PhD, Executive Advisor, Century Therapeutics

  • use Natural Killer cells to elicit long-term immune response, T-cells,
  • active Beta cells]Regulatory monitoring use
  • DM – regulatory cells made from Stem cells
  • mission durable response
  • Clinical issues – not easy way for treatment wiht a cell line and bioreactors and modalities less similar to autologoous celles
  • CAR-T in oncology lessons now are transferred to Immune disease
  • Cell therapy requires technologies to mature multiple modalities and multiple drugs not one cell therapy for all immune diseases
  • Stability of the therapy vs rejection by immune system
  • FDA making cells is not as making drugs – higher level of scrutiny for cell therapy
  • SYNTHETIC BIOLOGY on B-cells for future breakthrough

Samantha Singer, President & CEO, Abata Therapeutics

  • Immune response involve many cell types in many diseases
  • Oncology the use of T-cells as tissue residents staying in tissue long time
  • Specific biology of the disease and regulatory cells receptors optimizing TCR presentation in pathology of tissue residents phyno types
  • activate in nervous system or in pancreas – intersection of cell biology with disease biology
  • Market feasibility – scaling, biology, pathology for reimbursement
  • antibody therapy may be appropriate than cell therapy is only a novel option
  • Cell manufacturing requires optimization of process, companies commercializing across all cell types
  • comprehensive approach for systemic immune suppression
  • : healthy tissue vs diseased tissue with cell theray implanted cells as residents in tissue
  • clinical data on product performance and on the biology reactions

11:00 AM – 11:40 AM

Picasso Ballroom

Unmet Clinical Needs: 100 Harvard KOLs Weigh In

Moderators

Jose Florez, MD, PhD, Physician-in-Chief and Chair, Department of Medicine, Massachusetts General Hospital; Professor, Harvard Medical School

  • 40 minutes to deal with big needs collected from 100 faculties at Harvard Medical School
  • The ten issues on one slide
  • How could we use compute to distill data

Bruce Levy, MD, Physician-In-Chief and Co-Chair, Department of Medicine, Brigham and Women’s Hospital; Parker B. Francis Professor of Medicine, Harvard Medical School

  • Transformation from the Present to the Future
  • identifying the needs
  • Infectious diseases: Rapid diagnostics need
  • resistance to antibiotics and metabolic reactions endogenous
  • Pandemics globally of diseases erradicated in the past: Pox, polio
  • Improving health in Geriatrics, not population growing but geriatric population growing. Beyong age 60 a citizen will use 1 or 2 physicians each
  • 7,000 diseases, Genetic diseases requires integration and innovations in therapy
  • Innovations in Home devices

Panelists

Rox Anderson, MD, Lancer Endowed Chair of Dermatology;, Director, Wellman Center for Photomedicine, MGH; Professor of Dermatology, HMS

  • Access to data across institutions

Nicole Davis, PhD, Biomedical Communications

  • We asked 104 expert practitioners, content collected was analyzed
  1. detection early
  2. keeping the Human brain healthy
  3. geriatrics Medicine, aging and compound effects on health system with aging and Health equity
  • Bias in Data

Jean-François Formela, MD, Partner, Atlas Venture

  • genetic information used in therapeutics design

Steven Greenberg, MD, Neurologist, Brigham and Women’s Hospital; Professor of Neurology, Harvard Medical School

  • Human genome completed in 1999, human genetic diseases were discovered learn about the disease at the tissue level with genomics and a system approach
  • Pathogenic drivers, systme integration by therapeutics approaches to pathways multiple cytokines in allergic reactions Pfizer had two biomarkers and therapies for systemic biology of disease
  • Pediatrics has its own challenges
  • Imaging medicine
  • Living longer at a lower cost  – HOW TO ACHIEVE THAT?
  • growth abnormality in children: Body growth and Skull shrink

John Lepore, MD, CEO, ProFound Therapeutics;, CEO-Partner, Flagship Pioneering

  • Pathway, targeting therapy to patients in a System biological approach
  • Database of systme biology has missing components not included in the Human genome project – completion of the Data
  • Definition of End points needs revisiting
  • Identifying specific populations vs getting quickly to market
  • Diseases of aging: Muscles diseases – how to promote improvement in muscle mass

CONCLUSIONS

  1. Gray Tsunami
  2. Brain health
  3. Cancer treatment paradigm shift
  4. Fibrosis in many diseases
  5. infectious disease in changing World
  6. Equity in HC
  7. Clinical Data is VAST
  8. Systemic view of Human disease
  9. New approaches to Psychaitry
  10. Rare disease treatment needs a charter

In addition,

  • new generation of pain treatment
  • skin treatment new drugs
  • Chronic disease: improve treatment and prevention.
  • Obesity medicine – new discipline in a new Era

11:45 AM – 12:30 PM

Picasso Ballroom

Fireside

Fireside Chat

Moderators

Tazeen Ahmad, SMid-Cap Biotech Analyst, BofA Global Research

  • FDA sets criteria  – How is that done?
  • Autoimmune disease therapies – What is in the horizon?

 

Paul Anderson, MD, PhD, Chief Academic Officer, Mass General Brigham;

  • drug development
  • drug pricing in Europe
  • New book
  • RA needs more medicines

UNCONTROLLED SPREAD

In Uncontrolled Spread, a New York Times Best Seller, Dr. Scott Gottlieb identifies the reasons why the US was caught unprepared for the pandemic and how the country can improve its strategic planning to prepare for future viral threats.

Panelist

Scott Gottlieb, MD, Physician; Former Commissioner, Food and Drug Administration (2017-2019)

  • FDA approval 1st gene therapy in his tenure
  • Price of drugs: efficatious vs time to deveop
  • competitors in the marketplace are there for market share
  • New Book: Episodes in the FDA, appproval process at FDA, Gene therapy 1st in class approved – a special moment. Back in 1980s era translated to antibodies, to T-cell pioneering work.
  • Publisher worried it will not sell very well
  • FDA had concerns about manufacturing aspects
  • In 2024 we understand Biologics on novel platforms
  • Worries that Medicare will not reimbursement  and cover the new therapies: Cell therapy
  • Statins approval had a known very large market vs Cell therapy not known which Cancer patients will benefit???
  • Black box involved in Autoimmune, studies bring exciting results
  • In 2018 – needs arise for early approved of drugs in AD, amyloid plaque – change in thinking and is controversial
  • In early 2020, change in settings of clinical trials, placido no more the only way for Randomized trials
  • Approval for AD drug vs othe indication – the process is difference (DMD a case to think about)
  • AI & NLP: Train on data of 10,000 lesions
  • FDA choose not to regulate AI the physician is in the Middle
  • Who is wrong: CHatGPT or the clinician ?
  • Data set on gene may represents NEW biologies that Physicians had not seen before
  • Data validation on medical devices and their approval after regulating them
  • Diagnostics tests: Validation Panels are involved
  • Regulated on input data vs Output data and validate the input data
  • Platforms are needed for regulation of AI involvement in the drug discovery and the drug approval process
  • investment in this platforms will be done by Whom?? It will come
  • Framework for AI at FDA: Regulatory gray data for applications and standards for output – not a novel regulatory concept
  • If AI will be applied widely, I/O accuracy is a must have
  • may be achievable soon?
  • FDA is evolutionary organization in its decision process NOT a REVOLUTIONARY organization. Simulation work started in 2003, 40 people doing that then.
  • Recently, new team in Agency working of Safety with tools and technologies that are common in Science  – Approvals to drug labels and off labels that 20 years ago would not have happened
  • Tolerance for higher prices is to support Private sector that brings the innovating drugs to market

 

SPEAKERS

C-Suite Speakers

Faraz Ali

CEO, Tenaya Therapeutics

Peter Anastasiou

CEO, Capsida Biotherapeutics

Paul Anderson, MD, PhD

Chief Academic Officer, Mass General Brigham; K. Frank Austen Professor of Medicine, Harvard Medical School

Rahul Ballal, PhD

CEO, Mediar Therapeutics

Stéphane Bancel

CEO, Moderna

Craig Basson MD, PhD

Chief Medical Officer, Bitterroot Bio

Jeff Bluestone, PhD

CEO & President, Sonoma Biotherapeutics

Albert Bourla, PhD

Chairman & CEO, Pfizer

O’Neil Britton, MD

Chief Integration Officer & Executive Vice President, Mass General Brigham

Marc Casper

Chairman, President & CEO, Thermo Fisher Scientific

Joshua Cohen

Co-CEO, Amylyx Pharmaceuticals

Delos “Toby” Cosgrove, MD

Executive Advisor; former CEO & President, Cleveland Clinic

Jatin Dave, MD

Chief Medical Officer, MassHealth; Director of Clinical Affairs, UMass Chan Medical School

Punit Dhillon

CEO, Skye Bioscience

Steve Favaloro

Chairman & CEO, Genezen

John Fish

Chairman & CEO, Suffolk

Alexandria Forbes, PhD

CEO, MeiraGTx

Niyum Gandhi

CFO & Treasurer, Mass General Brigham

Chris Garabedian

Chairman & CEO, Xontogeny; Venture Portfolio Manager, Perceptive Advisors

Lucas Harrington, PhD

Co-Founder & CSO, Mammoth Biosciences

Marc Harrison, MD

Co-founder & CEO, Health Assurance Transformation Corp. (HATCo)

Amos Hedt

Chief Business Strategy Officer, Perspective Therapeutics

Rod Hochman, MD

President & CEO, Providence

David Hyman, MD

Chief Medical Officer, Eli Lilly and Company

Philip Kantoff, MD

Co-Founder & CEO, Convergent Therapeutics

Daniel Karlin, MD

Chief Medical Officer, MindMed

Reshma Kewalramani, MD

CEO & President, Vertex Pharmaceuticals

Justin Klee

Co-CEO, Amylyx Pharmaceuticals

Anne Klibanski, MD

President & CEO, Mass General Brigham; Laurie Carrol Guthart Professor of Medicine, Harvard Medical School

Samarth Kulkarni, PhD

CEO, CRISPR Therapeutics

Liz Kwo, MD

Chief Commercial Officer, Everly Health

Adam Landman, MD

Chief Information Officer & SVP, Digital, Mass General Brigham; Associate Professor of Emergency Medicine, Harvard Medical School

Chemu Lang’at

Chief Operating Officer, Best Buy Health

Paul LaViolette

Managing Partner & COO, SV Health Investors

John Lepore, MD

CEO, ProFound Therapeutics; CEO-Partner, Flagship Pioneering

Christopher Longhurst, MD

Chief Medical & Digital Officer, UC San Diego Health

Kevin Mahoney

CEO, University of Pennsylvania Health System

Niall Martin, PhD

CEO, Artios Pharma

James Mawson

CEO, Global Corporate Venturing

Mark McKenna

Chairman & CEO, Mirador Therapeutics

Jane Moran

Chief Information and Digital Officer, Mass General Brigham

William Morris, MD

Chief Medical Information Officer, Google Cloud

Rohan Palekar

CEO, 89bio

Raju Prasad, PhD

Chief Financial Officer, CRISPR Therapeutics

Xiayang Qiu, PhD

CEO, Regor Therapeutics

Harith Rajagopalan MD, PhD

CEO & Co-Founder, Fractyl Health

Shiv Rao, MD

CEO & Founder, Abridge

Kerry Ressler, MD, PhD

Chief Scientific Officer, McLean Hospital; Professor of Psychiatry, Harvard Medical School

Matthew Roden, PhD

President & CEO, Aktis Oncology

Sandi See Tai, MD

Chief Development Officer, Lexeo Therapeutics

Samantha Singer

President & CEO, Abata Therapeutics

Joanne Smith-Farrell, PhD

CEO & Director, Be Biopharma

Emma Somers-Roy

Chief Investment Officer, Mass General Brigham

Adam Steensberg, MD

President & CEO, Zealand Pharma

Tadaaki Taniguchi, MD, PhD

Chief Medical Officer, Astellas Pharma

Elsie Taveras, MD

Chief Community Health & Health Equity Officer, Mass General Brigham; Conrad Taff Endowed Chair and Professor of Pediatrics, Harvard Medical School

Jo Viney, PhD

Cofounder, President & CEO, Seismic Therapeutic

Ron Walls, MD

Chief Operating Officer, Mass General Brigham; Neskey Family Professor of Emergency Medicine, Harvard Medical School

Christophe Weber

President & CEO, Takeda

Fraser Wright, PhD

Chief Gene Therapy Officer, Kriya Therapeutics

Speakers

Anna Åsberg

Vice President, AstraZeneca Pharmaceuticals

Tazeen Ahmad

SMid-Cap Biotech Analyst, BofA Global Research

Jessica Allegretti, MD

Director, Crohn’s and Colitis Center, Brigham and Women’s Hospital; Associate Professor of Medicine, Harvard Medical School

Rox Anderson, MD

Lancer Endowed Chair of Dermatology; Director, Wellman Center for Photomedicine, MGH; Professor of Dermatology, HMS

Katherine Andriole, PhD

Director of Academic Research and Education, Mass General Brigham Data Science Office; Associate Professor, Harvard Medical School

Caroline Apovian, MD

Co-Director, Center for Weight Management and Wellness, Brigham and Women’s Hospital; Professor of Medicine, Harvard Medical School

Vanita Aroda, MD

Director, Diabetes Clinical Research, Brigham and Women’s Hospital; Associate Professor, Harvard Medical School

Natalie Artzi, PhD

Associate Professor of Medicine, Brigham and Women’s Hospital & Harvard Medical School

John Bishai, PhD

Global Healthcare Investment Banking, BofA Securities

David Blumenthal, MD

Professor of Practice of Public Health and Health Policy, Harvard TH Chan School of Public Health; Research Fellow, Harvard Kennedy School of Government; Samuel O. Thier Professor of Medicine, Emeritus, Harvard Medical School

Giles Boland, MD

President, Brigham and Women’s Hospital and Brigham and Women’s Physicians Organization; Philip H. Cook Distinguished Professor of Radiology, Harvard Medical School

Andrew Bressler

Washington Healthcare Policy Analyst, BofA Global Research

James Brink, MD

Enterprise Chief, Radiology, Mass General Brigham; Juan M. Taveras Professor of Radiology, Harvard Medical School

David Brown, MD

President, Academic Medical Centers, Mass General Brigham; Mass General Trustees Professor of Emergency Medicine, Harvard Medical School

Tyler Bryson

Corporate Vice President, US Health & Public Sector Industries, Microsoft Corporation

Jonathan Carlson, MD, PhD

Director of Chemistry, Center for Systems Biology, Massachusetts General Hospital; Assistant Professor of Medicine, Harvard Medical School

Miceal Chamberlain

President of Massachusetts, Bank of America

Moitreyee Chatterjee-Kishore, PhD

Head of Development, Immuno-Oncology and Cancer Cell Therapy, Astellas Pharma Inc.

Dong Feng Chen, MD, PhD

Associate Scientist, Massachusetts Eye and Ear; Associate Professor, Harvard Medical School

Jasmeer Chhatwal, MD, PhD

Associate Neurologist, Massachusetts General Hospital; Associate Professor of Neurology, Harvard Medical School

E. Antonio Chiocca, MD, PhD

Chair, Department of Neurosurgery, Brigham and Women’s Hospital; Harvey W. Cushing Professor of Neurosurgery, Harvard Medical School

Bryan Choi, MD, PhD

Associate Director, Center for Brain Tumor Immunology and Immunotherapy, Massachusetts General Hospital; Assistant Professor of Neurosurgery, Harvard Medical School

Deepak Chopra, MD

Founder, The Chopra Foundation

Yolonda Colson, MD, PhD

Chief, Division of Thoracic Surgery, Massachusetts General Hospital; Hermes C. Grillo Professor of Surgery, Harvard Medical School

Chad Cowan, PhD

Executive Advisor, Century Therapeutics

Cristina Cusin, MD

Director, MGH Ketamine Clinic and Psychiatrist, Depression Clinical and Research Program, Massachusetts General Hospital; Associate Professor in Psychiatry, Harvard Medical School

Nicole Davis, PhD

Biomedical Communications

Marcela del Carmen, MD

President, Massachusetts General Hospital and Massachusetts General Physicians Organization (MGPO); Executive Vice President, Mass General Brigham; Professor of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School

Gerard Doherty, MD

Surgeon-in-Chief, Mass General Brigham Cancer; Surgeon-in-Chief, Brigham and Women’s Hospital; Moseley Professor of Surgery, Harvard Medical School

Liz Everett Krisberg

Head of Bank of America Institute

Maurizio Fava, MD

Chair, Department of Psychiatry, Massachusetts General Hospital; Slater Family Professor of Psychiatry, Harvard Medical School

Keith Flaherty, MD

Director of Clinical Research, Mass General Cancer Center; Professor of Medicine, Harvard Medical School

Jose Florez, MD, PhD

Physician-in-Chief and Chair, Department of Medicine, Massachusetts General Hospital; Professor, Harvard Medical School

Jean-François Formela, MD

Partner, Atlas Venture

Fritz François, MD

Executive Vice President and Vice Dean, Chief of Hospital Operations, NYU Langone Health

Joanna Gajuk

Health Care Facilities and Managed Care Analyst, BofA Global Research

Jason Gerberry

Specialty Pharma and SMid-Cap Biotech Analyst, BofA Global Research

Gad Getz, PhD

Director of Bioinformatics, Krantz Center for Cancer Research and Department of Pathology; Paul C. Zamecnik Chair in Cancer Research, Mass General Cancer Center; Professor of Pathology, Harvard Medical School

Alexandra Golby, MD

Neurosurgeon; Director of Image-guided Neurosurgery, Brigham and Women’s Hospital; Professor of Neurosurgery, Professor of Radiology, Harvard Medical School

Allan Goldstein, MD

Chief of Pediatric Surgery, Massachusetts General Hospital; Surgeon-in-Chief, Mass General for Children; Marshall K. Bartlett Professor of Surgery, Harvard Medical School

Scott Gottlieb, MD

Physician; Former Commissioner, Food and Drug Administration (2017-2019)

David Grayzel, MD

Partner, Atlas Venture

Steven Greenberg, MD

Neurologist, Brigham and Women’s Hospital; Professor of Neurology, Harvard Medical School

Steven Grinspoon, MD

Chief, Metabolism Unit, Massachusetts General Hospital; Professor of Medicine, Harvard Medical School

Daphne Haas-Kogan, MD

Chief, Enterprise Radiation Oncology, Mass General Brigham; Professor, Harvard Medical School

Roger Hajjar, MD

Director, Gene & Cell Therapy Institute, Mass General Brigham

John Hanna, MD, PhD

Associate Professor, Brigham and Women’s Hospital & Harvard Medical School

Yvonne Hao

Secretary of Economic Development, Commonwealth of Massachusetts

Nobuhiko Hata PhD

Director, Surgical Navigation and Robotics Laboratory, Brigham and Women’s Hospital; Professor of Radiology, Harvard Medical School

Maura Healey

Governor of the Commonwealth of Massachusetts

Elizabeth Henske, MD

Director, Center for LAM Research and Clinical Care, Brigham and Women’s Hospital; Professor of Medicine, Harvard Medical School

Leigh Hochberg MD, PhD

Director of Neurotechnology and Neurorecovery, Massachusetts General Hospital; Senior Lecturer on Neurology, Harvard Medical School

Daphne Holt, MD, PhD

Director of the Resilience and Prevention Program, Massachusetts General Hospital; Associate Professor of Psychiatry, Harvard Medical School

Susan Huang, MD

EVP, Chief Executive, Providence Clinical Network, Providence Southern CA

Keith Isaacson, MD

Director of Minimally Invasive Gynecologic Surgery and Infertility, Newton Wellesley Hospital; Associate Professor of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School

Ole Isacson, MD-PhD

Founding Director, Neuroregeneration Research Institute, McLean Hospital; Professor of Neurology and Neuroscience, Harvard Medical School

Haim Israel

Head of Global Thematic Investing Research, BofA Global Research

Farouc Jaffer, MD, PhD

Director, Coronary Intervention, Massachusetts General Hospital; Associate Professor of Medicine, Harvard Medical School

Russell Jenkins, MD, PhD

Krantz Family Center for Cancer Research, Massachusetts General Hospital; Mass General Cancer Center, Center for Melanoma; Assistant Professor of Medicine, Harvard Medical School

Hadine Joffe, MD

Executive Director of the Connors Center for Women’s Health and Gender Biology; Interim Chair, Department of Psychiatry, Brigham and Women’s Hospital; Paula A. Johnson Professor of Psychiatry in the Field of Women’s Health, Harvard Medical School

Benjamin Kann, MD

Assistant Professor, Brigham and Women’s Hospital & Harvard Medical School

Tatsuo Kawai, MD, PhD

Director of the Legorreta Center for Clinical Transplantation Tolerance, A.Benedict Cosimi Chair in Transplant Surgery, Massachusetts General Hospital; Professor of Surgery, Harvard Medical School

Albert Kim, MD

Assistant Physician, Mass General Cancer Center; Assistant Professor, Harvard Medical School

Roger Kitterman

Senior Vice President, Ventures and Business Development & Licensing, Mass General Brigham Managing Partner, Mass General Brigham Ventures

Lotte Bjerre Knudsen, DMSc

Chief Scientific Advisor, Novo Nordisk

Vesela Kovacheva, MD, PhD

Director of Translational and Clinical Research, Mass General Brigham; Assistant Professor of Anesthesia, Harvard Medical School

Jonathan Kraft

President, The Kraft Group; Board Chair, Massachusetts General Hospital

John Krystal, MD

Chair, Department of Psychiatry, Yale School of Medicine

Daniel Kuritzkes, MD

Chief, Division of Infectious Diseases, Brigham and Women’s Hospital; Harriet Ryan Albee Professor of Medicine, Harvard Medical School

Bruce Levy, MD

Physician-In-Chief and Co-Chair, Department of Medicine, Brigham and Women’s Hospital; Parker B. Francis Professor of Medicine, Harvard Medical School

Katherine Liao, MD

Associate Physician, Department of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital; Associate Professor of Medicine and Biomedical Informatics, Harvard Medical School

David Louis, MD

Enterprise Chief, Pathology, Mass General Brigham Benjamin Castleman Professor of Pathology, Harvard Medical School

Tim Luker, PhD

VP, Ventures & West Coast Head, Eli Lilly

Andrew Luster, MD, PhD

Chief, Division of Rheumatology, Allergy and Immunology; Director, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital; Persis, Cyrus and Marlow B. Harrison Professor of Medicine, Harvard Medical School

Allen Lutz

Health Care Services Analyst, BofA Global Research

Calum MacRae MD, PhD

Vice Chair for Scientific Innovation, Department of Medicine, Brigham and Women’s Hospital; Professor of Medicine, Harvard Medical School

Joren Madsen, MD, PhD

Director, MGH Transplant Center; Paul S. Russell/Warner-Lambert Professor of Surgery, Harvard Medical School

Faisal Mahmood, PhD

Associate Professor, Brigham and Women’s Hospital & Harvard Medical School

Peter Marks, MD, PhD

Director, Center for Biologics Evaluation and Research, FDA

Marcela Maus, MD, PhD

Director of Cellular Therapy and Paula O’Keeffe Chair in Cancer Research, Krantz Family Center for Cancer Research and Mass General Cancer Center; Associate Director, Gene and Cell Therapy Institute, Mass General Brigham; Associate Professor, Harvard Medical School

Thorsten Mempel, MD, PhD

Associate Director, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital; Professor of Medicine, Harvard Medical School

Rebecca Mishuris, MD

Chief Medical Information Officer, Mass General Brigham; Member of the Faculty, Harvard Medical School

Pradeep Natarajan, MD

Director of Preventive Cardiology, Paul & Phyllis Fireman Endowed Chair in Vascular Medicine, Massachusetts General Hospital; Associate Professor of Medicine, Harvard Medical School

Nawal Nour, MD

Chair, Department of Obstetrics and Gynecology, Brigham and Women’s Hospital; Associate Professor, Kate Macy Ladd Professorship, Harvard Medical School

Heather O’Sullivan, MS, RN, AGNP

President, Mass General Brigham Healthcare at Home

Anne Oxrider

Senior Vice President, Benefits Executive, Bank of America

Claire-Cecile Pierre, MD

Vice President, Community Health Programs, Mass General Brigham; Instructor in Medicine, Harvard Medical School

Richard Pierson III, MD

Scientific Director, Center for Transplantation Sciences, Massachusetts General Hospital; Professor of Surgery, Harvard Medical School

Mark Poznansky, MD, PhD

Director, Vaccine and Immunotherapy Center, Massachusetts General Hospital; Steve and Deborah Gorlin MGH Research Scholar; Professor of Medicine, Harvard Medical School

Yakeel Quiroz, PhD

Director, Familial Dementia Neuroimaging Lab and Director, Multicultural Alzheimer’s Prevention Program, Massachusetts General Hospital; Paul B. and Sandra M. Edgerley MGH Research Scholar; Associate Professor, Harvard Medical School

Heidi Rehm, PhD

Chief Genomics Officer, Massachusetts General Hospital; Professor of Pathology, Harvard Medical School

Leonardo Riella, MD, PhD

Medical Director of Kidney Transplantation, Massachusetts General Hospital; Harold and Ellen Danser Endowed Chair in Transplantation, Harvard Medical School

Jorge Rodriguez, MD

Clinician-investigator, Brigham and Women’s Hospital; Assistant Professor, Harvard Medical School

Adam Ron

Health Care Facilities and Managed Care Analyst, BofA Global Research

David Ryan, MD

Physician-in-Chief, Mass General Brigham Cancer; Professor of Medicine, Harvard Medical School

Michael Ryskin

Life Science Tools & Diagnostics Analyst, BofA Global Research

Alkesh Shah

Head of US Equity Software Research, BofA Global Research

Angela Shen, MD

Vice President, Strategic Innovation Leaders, Mass General Brigham Innovation

Gregory Simon

President, Simonovation

Prabhjot Singh, MD, PhD

Senior Advisor, Strategic Initiatives Peterson Health Technology Institute

Brendan Singleton

Healthcare Equity Capital Markets, BofA Securities

Caroline Sokol, MD, PhD

Assistant Physician, Massachusetts General Hospital; Assistant Professor, Harvard Medical School

Daniel Solomon, MD

Matthew H. Liang Distinguished Chair in Arthritis and Population Health, Brigham and Women’s Hospital; Professor of Medicine, Harvard Medical School

Scott Solomon, MD

Director, Clinical Trials Outcomes Center; Edward D. Frohlich Distinguished Chair in Cardiovascular Pathophysiology, Brigham and Women’s Hospital; Professor of Medicine, Harvard Medical School

Fatima Cody Stanford, MD

Obesity Medicine Physician Scientist, Massachusetts General Hospital; Associate Professor of Medicine and Pediatrics, Harvard Medical School

Shannon Stott, PhD

Associate Investigator, Krantz Family Center for Cancer Research and Mass General Cancer Center; d’Arbeloff Research Scholar, Massachusetts General Hospital; Associate Investigator, Krantz Family Center for Cancer Research Harvard Medical School

Alec Stranahan, PhD

SMid-Cap Biotech Analyst, BofA Global Research

Marc Succi, MD

Executive Director, Mass General Brigham MESH Incubator; Associate Chair of Innovation & Commercialization, Mass General Brigham Radiology; Assistant Professor, Harvard Medical School

Guillermo Tearney, MD, PhD

Principal Investigator, Wellman Center for Photomedicine, Massachusetts General Hospital; Remondi Family Endowed MGH Research Institute Chair; Professor of Pathology, Harvard Medical School

David Ting, MD

Associate Clinical Director for Innovation, Mass General Cancer Center; Associate Professor of Medicine, Harvard Medical School

Raul Uppot, MD

Interventional Radiologist, Massachusetts General Hospital; Associate Professor, Harvard Medical School

Chris Varma, PhD

Co-founder, Chairman & CEO, Frontier Medicines

Kaveeta Vasisht, MD, PharmD

Associate Commissioner, Women’s Health, U.S. Food and Drug Administration

Alexandra-Chloé Villani PhD

Investigator, Massachusetts General Hospital; Assistant Professor, Harvard Medical School

Kate Walsh

Secretary of Health and Human Services, State of Massachusetts

David Walt, PhD

Professor of Pathology, Brigham and Women’s Hospital; Hansjörg Wyss Professor of Biologically Inspired Engineering, Harvard Medical School

Jennifer Warner-Schmidt, PhD

Vice President, Scientific Affairs, Transcend Therapeutics

Renee Wegrzyn, PhD

Director, Advanced Research Projects Agency for Health

Christoph Westphal, MD, PhD

General Partner, Longwood Fund

Deborah Wexler, MD

Chief, Diabetes Unit, Massachusetts General Hospital; Associate Professor of Medicine, Harvard Medical School

Charlie Yang, PhD

Large/SMid-Cap Biotech and Major Pharma Analyst, BofA Global Research

Nathan Yozwiak, PhD

Head of Research, Gene and Cell Therapy Institute, Mass General Brigham

Jason Zemansky, PhD

SMid-Cap Biotech Analyst, BofA Global Research

Alice Zheng, MD

Principal, RH Capital

We continue to confirm more speakers. Please check back regularly for updates.

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Eight Subcellular Pathologies driving Chronic Metabolic Diseases – Methods for Mapping Bioelectronic Adjustable Measurements as potential new Therapeutics: Impact on Pharmaceuticals in Use

Eight Subcellular Pathologies driving Chronic Metabolic Diseases – Methods for Mapping Bioelectronic Adjustable Measurements as potential new Therapeutics: Impact on Pharmaceuticals in Use

Curators:

 

THE VOICE of Aviva Lev-Ari, PhD, RN

In this curation we wish to present two breaking through goals:

Goal 1:

Exposition of a new direction of research leading to a more comprehensive understanding of Metabolic Dysfunctional Diseases that are implicated in effecting the emergence of the two leading causes of human mortality in the World in 2023: (a) Cardiovascular Diseases, and (b) Cancer

Goal 2:

Development of Methods for Mapping Bioelectronic Adjustable Measurements as potential new Therapeutics for these eight subcellular causes of chronic metabolic diseases. It is anticipated that it will have a potential impact on the future of Pharmaceuticals to be used, a change from the present time current treatment protocols for Metabolic Dysfunctional Diseases.

According to Dr. Robert Lustig, M.D, an American pediatric endocrinologist. He is Professor emeritus of Pediatrics in the Division of Endocrinology at the University of California, San Francisco, where he specialized in neuroendocrinology and childhood obesity, there are eight subcellular pathologies that drive chronic metabolic diseases.

These eight subcellular pathologies can’t be measured at present time.

In this curation we will attempt to explore methods of measurement for each of these eight pathologies by harnessing the promise of the emerging field known as Bioelectronics.

Unmeasurable eight subcellular pathologies that drive chronic metabolic diseases

  1. Glycation
  2. Oxidative Stress
  3. Mitochondrial dysfunction [beta-oxidation Ac CoA malonyl fatty acid]
  4. Insulin resistance/sensitive [more important than BMI], known as a driver to cancer development
  5. Membrane instability
  6. Inflammation in the gut [mucin layer and tight junctions]
  7. Epigenetics/Methylation
  8. Autophagy [AMPKbeta1 improvement in health span]

Diseases that are not Diseases: no drugs for them, only diet modification will help

Image source

Robert Lustig, M.D. on the Subcellular Processes That Belie Chronic Disease

https://www.youtube.com/watch?v=Ee_uoxuQo0I

 

Exercise will not undo Unhealthy Diet

Image source

Robert Lustig, M.D. on the Subcellular Processes That Belie Chronic Disease

https://www.youtube.com/watch?v=Ee_uoxuQo0I

 

These eight Subcellular Pathologies driving Chronic Metabolic Diseases are becoming our focus for exploration of the promise of Bioelectronics for two pursuits:

  1. Will Bioelectronics be deemed helpful in measurement of each of the eight pathological processes that underlie and that drive the chronic metabolic syndrome(s) and disease(s)?
  2. IF we will be able to suggest new measurements to currently unmeasurable health harming processes THEN we will attempt to conceptualize new therapeutic targets and new modalities for therapeutics delivery – WE ARE HOPEFUL

In the Bioelecronics domain we are inspired by the work of the following three research sources:

  1. Biological and Biomedical Electrical Engineering (B2E2) at Cornell University, School of Engineering https://www.engineering.cornell.edu/bio-electrical-engineering-0
  2. Bioelectronics Group at MIT https://bioelectronics.mit.edu/
  3. The work of Michael Levin @Tufts, The Levin Lab
Michael Levin is an American developmental and synthetic biologist at Tufts University, where he is the Vannevar Bush Distinguished Professor. Levin is a director of the Allen Discovery Center at Tufts University and Tufts Center for Regenerative and Developmental Biology. Wikipedia
Born: 1969 (age 54 years), Moscow, Russia
Education: Harvard University (1992–1996), Tufts University (1988–1992)
Affiliation: University of Cape Town
Research interests: Allergy, Immunology, Cross Cultural Communication
Awards: Cozzarelli prize (2020)
Doctoral advisor: Clifford Tabin
Most recent 20 Publications by Michael Levin, PhD
SOURCE
SCHOLARLY ARTICLE
The nonlinearity of regulation in biological networks
1 Dec 2023npj Systems Biology and Applications9(1)
Co-authorsManicka S, Johnson K, Levin M
SCHOLARLY ARTICLE
Toward an ethics of autopoietic technology: Stress, care, and intelligence
1 Sep 2023BioSystems231
Co-authorsWitkowski O, Doctor T, Solomonova E
SCHOLARLY ARTICLE
Closing the Loop on Morphogenesis: A Mathematical Model of Morphogenesis by Closed-Loop Reaction-Diffusion
14 Aug 2023Frontiers in Cell and Developmental Biology11:1087650
Co-authorsGrodstein J, McMillen P, Levin M
SCHOLARLY ARTICLE
30 Jul 2023Biochim Biophys Acta Gen Subj1867(10):130440
Co-authorsCervera J, Levin M, Mafe S
SCHOLARLY ARTICLE
Regulative development as a model for origin of life and artificial life studies
1 Jul 2023BioSystems229
Co-authorsFields C, Levin M
SCHOLARLY ARTICLE
The Yin and Yang of Breast Cancer: Ion Channels as Determinants of Left–Right Functional Differences
1 Jul 2023International Journal of Molecular Sciences24(13)
Co-authorsMasuelli S, Real S, McMillen P
SCHOLARLY ARTICLE
Bioelectricidad en agregados multicelulares de células no excitables- modelos biofísicos
Jun 2023Revista Española de Física32(2)
Co-authorsCervera J, Levin M, Mafé S
SCHOLARLY ARTICLE
Bioelectricity: A Multifaceted Discipline, and a Multifaceted Issue!
1 Jun 2023Bioelectricity5(2):75
Co-authorsDjamgoz MBA, Levin M
SCHOLARLY ARTICLE
Control Flow in Active Inference Systems – Part I: Classical and Quantum Formulations of Active Inference
1 Jun 2023IEEE Transactions on Molecular, Biological, and Multi-Scale Communications9(2):235-245
Co-authorsFields C, Fabrocini F, Friston K
SCHOLARLY ARTICLE
Control Flow in Active Inference Systems – Part II: Tensor Networks as General Models of Control Flow
1 Jun 2023IEEE Transactions on Molecular, Biological, and Multi-Scale Communications9(2):246-256
Co-authorsFields C, Fabrocini F, Friston K
SCHOLARLY ARTICLE
Darwin’s agential materials: evolutionary implications of multiscale competency in developmental biology
1 Jun 2023Cellular and Molecular Life Sciences80(6)
Co-authorsLevin M
SCHOLARLY ARTICLE
Morphoceuticals: Perspectives for discovery of drugs targeting anatomical control mechanisms in regenerative medicine, cancer and aging
1 Jun 2023Drug Discovery Today28(6)
Co-authorsPio-Lopez L, Levin M
SCHOLARLY ARTICLE
Cellular signaling pathways as plastic, proto-cognitive systems: Implications for biomedicine
12 May 2023Patterns4(5)
Co-authorsMathews J, Chang A, Devlin L
SCHOLARLY ARTICLE
Making and breaking symmetries in mind and life
14 Apr 2023Interface Focus13(3)
Co-authorsSafron A, Sakthivadivel DAR, Sheikhbahaee Z
SCHOLARLY ARTICLE
The scaling of goals from cellular to anatomical homeostasis: an evolutionary simulation, experiment and analysis
14 Apr 2023Interface Focus13(3)
Co-authorsPio-Lopez L, Bischof J, LaPalme JV
SCHOLARLY ARTICLE
The collective intelligence of evolution and development
Apr 2023Collective Intelligence2(2):263391372311683SAGE Publications
Co-authorsWatson R, Levin M
SCHOLARLY ARTICLE
Bioelectricity of non-excitable cells and multicellular pattern memories: Biophysical modeling
13 Mar 2023Physics Reports1004:1-31
Co-authorsCervera J, Levin M, Mafe S
SCHOLARLY ARTICLE
There’s Plenty of Room Right Here: Biological Systems as Evolved, Overloaded, Multi-Scale Machines
1 Mar 2023Biomimetics8(1)
Co-authorsBongard J, Levin M
SCHOLARLY ARTICLE
Transplantation of fragments from different planaria: A bioelectrical model for head regeneration
7 Feb 2023Journal of Theoretical Biology558
Co-authorsCervera J, Manzanares JA, Levin M
SCHOLARLY ARTICLE
Bioelectric networks: the cognitive glue enabling evolutionary scaling from physiology to mind
1 Jan 2023Animal Cognition
Co-authorsLevin M
SCHOLARLY ARTICLE
Biological Robots: Perspectives on an Emerging Interdisciplinary Field
1 Jan 2023Soft Robotics
Co-authorsBlackiston D, Kriegman S, Bongard J
SCHOLARLY ARTICLE
Cellular Competency during Development Alters Evolutionary Dynamics in an Artificial Embryogeny Model
1 Jan 2023Entropy25(1)
Co-authorsShreesha L, Levin M
5

5 total citations on Dimensions.

Article has an altmetric score of 16
SCHOLARLY ARTICLE
1 Jan 2023BIOLOGICAL JOURNAL OF THE LINNEAN SOCIETY138(1):141
Co-authorsClawson WP, Levin M
SCHOLARLY ARTICLE
Future medicine: from molecular pathways to the collective intelligence of the body
1 Jan 2023Trends in Molecular Medicine
Co-authorsLagasse E, Levin M

THE VOICE of Dr. Justin D. Pearlman, MD, PhD, FACC

PENDING

THE VOICE of  Stephen J. Williams, PhD

Ten TakeAway Points of Dr. Lustig’s talk on role of diet on the incidence of Type II Diabetes

 

  1. 25% of US children have fatty liver
  2. Type II diabetes can be manifested from fatty live with 151 million  people worldwide affected moving up to 568 million in 7 years
  3. A common myth is diabetes due to overweight condition driving the metabolic disease
  4. There is a trend of ‘lean’ diabetes or diabetes in lean people, therefore body mass index not a reliable biomarker for risk for diabetes
  5. Thirty percent of ‘obese’ people just have high subcutaneous fat.  the visceral fat is more problematic
  6. there are people who are ‘fat’ but insulin sensitive while have growth hormone receptor defects.  Points to other issues related to metabolic state other than insulin and potentially the insulin like growth factors
  7. At any BMI some patients are insulin sensitive while some resistant
  8. Visceral fat accumulation may be more due to chronic stress condition
  9. Fructose can decrease liver mitochondrial function
  10. A methionine and choline deficient diet can lead to rapid NASH development

 

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The drug efflux pump MDR1 promotes intrinsic and acquired resistance to PROTACs in cancer cells

Reporter: Stephen J. Williams, PhD.
Below is one of the first reports  on the potential mechanisms of intrinsic and acquired resistance to PROTAC therapy in cancer cells.
Proteolysis-targeting chimeras (PROTACs) are a promising new class of drugs that selectively degrade cellular proteins of interest. PROTACs that target oncogene products are avidly being explored for cancer therapies, and several are currently in clinical trials. Drug resistance is a substantial challenge in clinical oncology, and resistance to PROTACs has been reported in several cancer cell models. Here, using proteomic analysis, we found intrinsic and acquired resistance mechanisms to PROTACs in cancer cell lines mediated by greater abundance or production of the drug efflux pump MDR1. PROTAC-resistant cells were resensitized to PROTACs by genetic ablation of ABCB1 (which encodes MDR1) or by coadministration of MDR1 inhibitors. In MDR1-overexpressing colorectal cancer cells, degraders targeting either the kinases MEK1/2 or the oncogenic mutant GTPase KRASG12C synergized with the dual epidermal growth factor receptor (EGFR/ErbB)/MDR1 inhibitor lapatinib. Moreover, compared with single-agent therapies, combining MEK1/2 degraders with lapatinib improved growth inhibition of MDR1-overexpressing KRAS-mutant colorectal cancer xenografts in mice. Together, our findings suggest that concurrent blockade of MDR1 will likely be required with PROTACs to achieve durable protein degradation and therapeutic response in cancer.

INTRODUCTION

Proteolysis-targeting chimeras (PROTACs) have emerged as a revolutionary new class of drugs that use cancer cells’ own protein destruction machinery to selectively degrade essential tumor drivers (1). PROTACs are small molecules with two functional ends, wherein one end binds to the protein of interest, whereas the other binds to an E3 ubiquitin ligase (23), bringing the ubiquitin ligase to the target protein, leading to its ubiquitination and subsequent degradation by the proteasome. PROTACs have enabled the development of drugs against previously “undruggable” targets and require neither catalytic activity nor high-affinity target binding to achieve target degradation (4). In addition, low doses of PROTACs can be highly effective at inducing degradation, which can reduce off-target toxicity associated with high dosing of traditional inhibitors (3). PROTACs have been developed for a variety of cancer targets, including oncogenic kinases (5), epigenetic proteins (6), and, recently, KRASG12C proteins (7). PROTACs targeting the androgen receptor or estrogen receptor are avidly being evaluated in clinical trials for prostate cancer (NCT03888612) or breast cancer (NCT04072952), respectively.
However, PROTACs may not escape the overwhelming challenge of drug resistance that befalls so many cancer therapies (8). Resistance to PROTACs in cultured cells has been shown to involve genomic alterations in their E3 ligase targets, such as decreased expression of Cereblon (CRBN), Von Hippel Lindau (VHL), or Cullin2 (CUL2) (911). Up-regulation of the drug efflux pump encoded by ABCB1—MDR1 (multidrug resistance 1), a member of the superfamily of adenosine 5′-triphosphate (ATP)–binding cassette (ABC) transporters—has been shown to convey drug resistance to many anticancer drugs, including chemotherapy agents, kinase inhibitors, and other targeted agents (12). Recently, PROTACs were shown to be substrates for MDR1 (1013), suggesting that drug efflux represents a potential limitation for degrader therapies. Here, using degraders (PROTACs) against bromodomain and extraterminal (BET) bromodomain (BBD) proteins and cyclin-dependent kinase 9 (CDK9) as a proof of concept, we applied proteomics to define acquired resistance mechanisms to PROTAC therapies in cancer cells after chronic exposure. Our study reveals a role for the drug efflux pump MDR1 in both acquired and intrinsic resistance to protein degraders in cancer cells and supports combination therapies involving PROTACs and MDR1 inhibitors to achieve durable protein degradation and therapeutic responses.

Fig. 1. Proteomic characterization of degrader-resistant cancer cell lines.
(A) Workflow for identifying protein targets up-regulated in degrader-resistant cancer cells. Single-run proteome analysis was performed, and changes in protein levels among parent and resistant cells were determined by LFQ. m/z, mass/charge ratio. (B and C) Cell viability assessed by CellTiter-Glo in parental and dBET6- or Thal SNS 032–resistant A1847 cells treated with increasing doses of dBET6 (B) or Thal SNS 032 (C) for 5 days. Data were analyzed as % of DMSO control, presented as means ± SD of three independent assays. Growth inhibitory 50% (GI50) values were determined using Prism software. (D to G) Immunoblotting for degrader targets and downstream signaling in parental A1847 cells and their derivative dBET6-R or Thal-R cells treated with increasing doses of dBET6 or Thal SNS 032 for 4 hours. The dBET6-R and Thal-R cells were continuously cultured in 500 nM PROTAC. Blots are representative, and densitometric analyses are means ± SD from three blots, each normalized to the loading control, GAPDH. DC50 values, quantitating either (E) the dose of dBET6 that reduces BRD2, BRD3, or BRD4 or (G) the dose of Thal SNS 032 that reduces CDK9 protein levels 50% of the DMSO control treatment, were determined with Prism software. Pol II, polymerase II. (H to K) Volcano plot of proteins with increased or reduced abundance in dBET6-R (H) or Thal-R (I) A1847 cells relative to parental cells. Differences in protein log2 LFQ intensities among degrader-resistant and parental cells were determined by paired t test permutation-based adjusted P values at FDR of <0.05 using Perseus software. The top 10 up-regulated proteins in each are shown in (J) and (K), respectively. FC, fold change. (L and M) ABCB1 log2 LFQ values in dBET6-R cells from (H) and Thal-R cells from (I) compared with those in parental A1847 cells. Data are presented as means ± SD from three independent assays. By paired t test permutation-based adjusted P values at FDR of <0.05 using Perseus software, ***P ≤ 0.001. (N) Cell viability assessed by CellTiter-Glo in parental and MZ1-resistant SUM159 cells treated with increasing doses of MZ1 for 5 days. Data were analyzed as % of DMSO control, presented as means of three independent assays. GI50 values were determined using Prism software. (O and P) Immunoblotting for degrader targets and downstream signaling in parental or MZ1-R SUM159 cells treated with increasing doses of MZ1 for 24 hours. The MZ1-R cells were continuously cultured in 500 nM MZ1. Blots are representative, and densitometric analyses are means ± SD from three blots, each normalized to the loading control, GAPDH. DC50 values were determined in Prism software. (Q and R) Top 10 up-regulated proteins (Q) and ABCB1 log2 LFQ values (R) in MZ1-R cells relative to parental SUM159 cells

Fig. 2. Chronic exposure to degraders induces MDR1 expression and drug efflux activity.
(A) ABCB1 mRNA levels in parental and degrader-resistant cell lines as determined by qRT-PCR. Data are means ± SD of three independent experiments. ***P ≤ 0.001 by Student’s t test. (B) Immunoblot analysis of MDR1 protein levels in parental and degrader-resistant cell lines. Blots are representative of three independent experiments. (C to E) Immunofluorescence (“IF”) microscopy of MDR1 protein levels in A1847 dBET6-R (C), SUM159 MZ1-R (D), and Thal-R A1847 cells (E) relative to parental cells. Nuclear staining by DAPI. Images are representative of three independent experiments. Scale bars, 100 μm. (F) Drug efflux activity in A1847 dBET6-R, SUM159 MZ1-R, and Thal-R A1847 cells relative to parental cells (Par.) using rhodamine 123 efflux assays. Bars are means ± SD of three independent experiments. ***P ≤ 0.001 by Student’s t test. (G) Intracellular dBET6 levels in parental or dBET-R A1847 cells transfected with a CRBN sensor and treated with increasing concentrations of dBET6. Intracellular dBET6 levels measured using the CRBN NanoBRET target engagement assay. Data were analyzed as % of DMSO control, presented as means ± SD of three independent assays. *P ≤ 0.05, **P ≤ 0.01, and ***P ≤ 0.001 by Student’s t test. (H and I) FISH analysis of representative drug-sensitive parental and drug-resistant A1847 (H) and SUM159 (I) cells using ABCB1 and control XCE 7 centromere probes. Images of interphase nuclei were captured with a Metasystems Metafer microscope workstation, and the raw images were extracted and processed to depict ABCB1 signals in magenta, centromere 7 signals in cyan, and DAPI-stained nuclei in blue. (J and K) CpG methylation status of the ABCB1 downstream promoter (coordinates: chr7.87,600,166-87,601,336) by bisulfite amplicon sequencing in parent and degrader-resistant A1847 (J) and SUM159 (K) cells. Images depict the averaged percentage of methylation for each region of the promoter, where methylation status is depicted by color as follows: red, methylated; blue, unmethylated. Schematic of the ABCB1 gene with the location of individual CpG sites is shown. Graphs are representative of three independent experiments. (L and M) Immunoblot analysis of MDR1 protein levels after short-term exposure [for hours (h) or days (d) as indicated] to BET protein degraders dBET6 or MZ1 (100 nM) in A1847 (L) and SUM159 (M) cells, respectively. Blots are representative of three independent experiments. (N to P) Immunoblot analysis of MDR1 protein levels in A1847 and SUM159 cells after long-term exposure (7 to 30 days) to BET protein degraders dBET6 (N), Thal SNS 032 (O), or MZ1 (P), each at 500 nM. Blots are representative of three independent experiments. (Q and R) Immunoblot analysis of MDR1 protein levels in degrader-resistant A1847 (Q) and SUM159 (R) cells after PROTAC removal for 2 or 7 days. Blots are representative of three independent experiments.

 

Fig. 3. Blockade of MDR1 activity resensitizes degrader-resistant cells to PROTACs.
(A and B) Cell viability by CellTiter-Glo assay in parental and degrader-resistant A1847 (A) and SUM159 (B) cells transfected with control siRNA or siRNAs targeting ABCB1 and cultured for 120 hours. Data were analyzed as % of control, presented as means ± SD of three independent assays. ***P ≤ 0.001 by Student’s t test. (C and D) Immunoblot analysis of degrader targets after ABCB1 knockdown in parental and degrader-resistant A1847 (C) and SUM159 (D) cells. Blots are representative, and densitometric analyses using ImageJ are means ± SD of three blots, each normalized to the loading control, GAPDH. (E) Drug efflux activity, using the rhodamine 123 efflux assay, in degrader-resistant cells after MDR1 inhibition by tariquidar (0.1 μM). Data are means ± SD of three independent experiments. ***P ≤ 0.001 by Student’s t test. (F to H) Cell viability by CellTiter-Glo assay in parental and dBET6-R (F) or Thal-R (G) A1847 cells or MZ1-R SUM159 cells (H) treated with increasing concentrations of tariquidar. Data are % of DMSO control, presented as means ± SD of three independent assays. GI50 value determined with Prism software. (I to K) Immunoblot analysis of degrader targets after MDR1 inhibition (tariquidar, 0.1 μM for 24 hours) in parental and degrader-resistant A1847 cells (I and J) and SUM159 cells (K). Blots are representative, and densitometric analyses are means ± SD from three blots, each normalized to the loading control, GAPDH. (L and M) A 14-day colony formation assessed by crystal violet staining of (L) A1847 cells or (M) SUM159 cells treated with degrader (0.1 μM; dBET6 or MZ1, respectively) and MDR1 inhibitor tariquidar (0.1 μM). Images are representative of three biological replicates. (N) Immunoblotting for MDR1 in SUM159 cells stably expressing FLAG-MDR1 after selection with hygromycin. (O) Long-term 14-day colony formation assay of SUM159 cells expressing FLAG-MDR1 that were treated with DMSO, MZ1 (0.1 μM), or MZ1 and tariquidar (0.1 μM) for 14 days, assessed by crystal violet staining. Representative images of three biological replicates are shown. (P and Q) RT-PCR (P) and immunoblot (Q) analysis of ABCB1 mRNA and MDR1 protein levels, respectively, in parental or MZ1-R HCT116, OVCAR3, and MOLT4 cells.

 

Fig. 4. Overexpression of MDR1 conveys intrinsic resistance to degrader therapies in cancer cells.
(A) Frequency of ABCB1 mRNA overexpression in a panel of cancer cell lines, obtained from cBioPortal for Cancer Genomics using Z-score values of >1.2 for ABCB1 mRNA levels (30). (B) Immunoblot for MDR1 protein levels in a panel of 10 cancer cell lines. Blots are representative of three independent experiments. (C) Cell viability by CellTiter-Glo assay in cancer cell lines expressing high or low MDR1 protein levels and treated with Thal SNS 032 for 5 days. Data were analyzed as % of DMSO control, presented as means ± SD of three independent assays. GI50 values were determined with Prism software. (D to F) Immunoblot analysis of CDK9 in MDR1-low (D) or MDR1-high (E) cell lines after Thal SNS 032 treatment for 4 hours. Blots are representative, and densitometric analyses using ImageJ are means ± SD from three blots, each normalized to the loading control, GAPDH. DC50 value determined with Prism. (G and H) Immunoblotting of control and MDR1-knockdown DLD-1 cells treated for 4 hours with increasing concentrations of Thal SNS 032 [indicated in (H)]. Blots are representative, and densitometric analysis data are means ± SD from three blots, each normalized to the loading control, GAPDH. DC50 value determined with Prism. (I) Drug efflux activity using rhodamine 123 efflux assays in DLD-1 cells treated with DMSO or 0.1 μM tariquidar. Data are means ± SD of three independent experiments. ***P ≤ 0.001 by Student’s t test. (J) Intracellular Thal SNS 032 levels, using the CRBN NanoBRET target engagement assay, in MDR1-overexpressing DLD-1 cells treated with DMSO or 0.1 μM tariquidar and increasing doses of Thal SNS 032. Data are % of DMSO control, presented as means ± SD of three independent assays. **P ≤ 0.01 and ***P ≤ 0.001 by Student’s t test. (K to N) Immunoblotting in DLD-1 cells treated with increasing doses of Thal SNS 032 (K and L) or dBET6 (M and N) alone or with tariquidar (0.1 μM) for 4 hours. Blots are representative, and densitometric analyses are means ± SD from three blots, each normalized to the loading control, GAPDH. DC50 value of Thal SNS 032 for CDK9 reduction (L) or of dBET6 for BRD4 reduction (N) determined with Prism. (O to T) Bliss synergy scores based on cell viability by CellTiter-Glo assay, colony formation, and immunoblotting in DLD-1 cells treated with the indicated doses of Thal SNS 032 (O to Q) or dBET6 (R to T) alone or with tariquidar. Cells were treated for 14 days for colony formation assays and 24 hours for immunoblotting.

 

Fig. 5. Repurposing dual kinase/MDR1 inhibitors to overcome degrader resistance in cancer cells.
(A and B) Drug efflux activity by rhodamine 123 efflux assays in degrader-resistant [dBET-R (A) or Thal-R (B)] A1847 cells after treatment with tariquidar, RAD001, or lapatinib (each 2 μM). Data are means ± SD of three independent experiments. *P ≤ 0.05 by Student’s t test. (C and D) CellTiter-Glo assay for the cell viability of parental, dBET6-R, or Thal-R A1847 cells treated with increasing concentrations of RAD001 (C) or lapatinib (D). Data were analyzed as % of DMSO control, presented as means ± SD of three independent assays. GI50 values were determined with Prism software. (E to I) Immunoblot analysis of degrader targets in parental (E), dBET6-R (F and G), and Thal-R (H and I) A1847 cells treated with increasing concentrations of RAD001 or lapatinib for 4 hours. Blots are representative, and densitometric analyses are means ± SD from three blots, each normalized to the loading control, GAPDH. DC50 value of dBET6 for BRD4 reduction (G) or of Thal SNS 032 for CDK9 reduction (I) determined with Prism. (J) Immunoblotting for cleaved PARP in dBET6-R or Thal-R A1847 cells treated with RAD001, lapatinib, or tariquidar (each 2 μM) for 24 hours. Blots are representative of three independent blots. (K to N) Immunoblotting for BRD4 in DLD-1 cells treated with increasing doses of dBET6 alone or in combination with either RAD001 or lapatinib [each 2 μM (K and L)] or KU-0063794 or afatinib [each 2 μM (M and N)] for 4 hours. Blots are representative of three independent experiments and, in (L), are means ± SD from three blots, each normalized to the loading control, GAPDH. DC50 value for BRD4 reduction (L) determined in Prism. (O) Colony formation by DLD-1 cells treated with DMSO, dBET6 (0.1 μM), lapatinib (2 μM), afatinib (2 μM), RAD001 (2 μM), KU-0063794 (2 μM), or the combination of inhibitor and dBET6 for 14 days. Images representative of three independent assays. (P and Q) Immunoblotting for CDK9 in DLD-1 cells treated with increasing doses of Thal SNS 032 and/or RAD001 (2 μM) or lapatinib (2 μM) for 4 hours. Blots are representative, and densitometric analyses are means ± SD from three blots, each normalized to the loading control, GAPDH. DC50 value for CDK9 reduction determined with Prism (Q). (R) Colony formation in DLD-1 cells treated with DMSO, Thal SNS 032 (0.5 μM), lapatinib (2 μM), and/or RAD001 (2 μM) as indicated for 14 days.

 

Fig. 6. Combining MEK1/2 degraders with lapatinib synergistically kills MDR1-overexpressing KRAS-mutant CRC cells and tumors.
(A and B) ABCB1 expression in KRAS-mutant CRC cell lines from cBioPortal (30) (A) and MDR1 abundance in select KRAS-mutant CRC cell lines (B). (C) Cell viability assessed by CellTiter-Glo in CRC cells treated with increasing doses of MS432 for 5 days, analyzed as % of DMSO control. GI50 value determined with Prism software. (D) Colony formation by CRC cells 14 days after treatment with 1 μM MS432. (E) MEK1/2 protein levels assessed by immunoblot in CRC lines SKCO1 (low MDR1) or LS513 (high MDR1) treated with increasing doses of MS432 for 4 hours. (F) Rhodamine 123 efflux in LS513 cells treated with DMSO, 2 μM tariquidar, or 2 μM lapatinib. (G and H) Immunoblotting analysis in LS513 cells treated with increasing doses of MS432 alone or in combination with tariquidar (0.1 μM) or lapatinib (5 μM) for 24 hours. DC50 value for MEK1 levels determined with Prism. (I) Immunoblotting in LS513 cells treated with DMSO, PD0325901 (0.01 μM), lapatinib (5 μM), or the combination for 48 hours. (J and K) Immunoblotting in LS513 cells treated either with DMSO, MS432 (1 μM), tariquidar (0.1 μM) (J), or lapatinib (5 μM) (K), alone or in combination. (L) Bliss synergy scores determined from cell viability assays (CellTiter-Glo) in LS513 cells treated with increasing concentrations of MS432, lapatinib, or the combination. (M and N) Colony formation by LS513 cells (M) and others (N) treated with DMSO, lapatinib (2 μM), MS432 (1 μM), or the combination for 14 days. (O and P) Immunoblotting in LS513 cells treated with increasing doses of MS934 alone (O) or combined with lapatinib (5 μM) (P) for 24 hours. (Q and R) Tumor volume of LS513 xenografts (Q) and the body weights of the tumor-bearing nude mice (R) treated with vehicle, MS934 (50 mg/kg), lapatinib (100 mg/kg), or the combination. n = 5 mice per treatment group. In (A) to (R), blots and images are representative of three independent experiments, and quantified data are means ± SD [SEM in (Q) and (R)] of three independent experiments; ***P ≤ 0.001 by Student’s t test.

 

Fig. 7. Lapatinib treatment improves KRASG12C degrader therapies in MDR1-overexpressing CRC cell lines.
(A and B) Colony formation by SW1463 (A) or SW837 (B) cells treated with DMSO, LC-2 (1 μM), or MRTX849 (1 μM) for 14 days. Images representative of three independent assays. (C to E) Immunoblotting in SW1463 cells (C and D) and SW837 cells (E) treated with DMSO, LC-2 (1 μM), tariquidar (0.1 μM) (C), or lapatinib (5 μM) (D and E) alone or in combination for 48 hours. Blots are representative of three independent experiments. (F and G) Bliss synergy scores based on CellTiter-Glo assay for the cell viability of SW1463 (F) or SW837 (G) cells treated with increasing concentrations of LC-2, lapatinib, or the combination. Data are means of three experiments ± SD. (H and I) Colony formation of SW1463 (H) or SW837 (I) cells treated as indicated (−, DMSO; LC-2, 1 μM; lapatinib, 2 μM; tariquidar, 0.1 μM) for 14 days. Images representative of three independent assays. (J) Rationale for combining lapatinib with MEK1/2 or KRASG12C degraders in MDR1-overexpressing CRC cell lines. Simultaneous blockade of MDR1 and ErbB receptor signaling overcomes degrader resistance and ErbB receptor kinome reprogramming, resulting in sustained inhibition of KRAS effector signaling.

SOURCE

Other articles in this Open Access Scientific Journal on PROTAC therapy in cancer include

Accelerating PROTAC drug discovery: Establishing a relationship between ubiquitination and target protein degradation

The Vibrant Philly Biotech Scene: Proteovant Therapeutics Using Artificial Intelligence and Machine Learning to Develop PROTACs

The Map of human proteins drawn by artificial intelligence and PROTAC (proteolysis targeting chimeras) Technology for Drug Discovery

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Live Conference Coverage AACR 2020 in Real Time: Monday June 22, 2020 Mid Day Sessions

Reporter: Stephen J. Williams, PhD

This post will be UPDATED during the next two days with notes from recordings from other talks

Follow Live in Real Time using

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@pharma_BI

@AACR

 

 

 

 

 

 

 

Register for FREE at https://www.aacr.org/

 

AACR VIRTUAL ANNUAL MEETING II

 

June 22-24: Free Registration for AACR Members, the Cancer Community, and the Public
This virtual meeting will feature more than 120 sessions and 4,000 e-posters, including sessions on cancer health disparities and the impact of COVID-19 on clinical trials

 

This Virtual Meeting is Part II of the AACR Annual Meeting.  Part I was held online in April and was centered only on clinical findings.  This Part II of the virtual meeting will contain all the Sessions and Abstracts pertaining to basic and translational cancer research as well as clinical trial findings.

 

REGISTER NOW

 

Pezcoller Foundation-AACR International Award for Extraordinary Achievement in Cancer Research

The prestigious Pezcoller Foundation-AACR International Award for Extraordinary Achievement in Cancer Research was established in 1997 to annually recognize a scientist of international renown who has made a major scientific discovery in basic cancer research OR who has made significant contributions to translational cancer research; who continues to be active in cancer research and has a record of recent, noteworthy publications; and whose ongoing work holds promise for continued substantive contributions to progress in the field of cancer. For more information regarding the 2020 award recipient go to aacr.org/awards.

John E. Dick, Enzo Galligioni, David A Tuveson

DETAILS

Awardee: John E. Dick
Princess Anne Margaret Cancer Center, Toronto, Ontario
For determining how stem cells contribute to normal and leukemic hematopoeisis
  • not every cancer cell equal in their Cancer Hallmarks
  • how do we monitor and measure clonal dynamics
  • Barnie Clarkson did pivotal work on this
  • most cancer cells are post mitotic but minor populations of cells were dormant and survive chemotherapy
  •  only one cell is 1 in a million can regenerate and transplantable in mice and experiments with flow cytometry resolved the question of potency and repopulation of only small percentage of cells and undergo long term clonal population
  • so instead of going to cell lines and using thousands of shRNA looked at clinical data and deconvoluted the genetic information (RNASeq data) to determine progenitor and mature populations (how much is stem and how much is mature populations)
  • in leukemic patients they have seen massive expansion of a single stem cell population so only need one cell in AML if the stem cells have the mutational hits early on in their development
  • finding the “seeds of relapse”: finding the small subpopulation of stem cells that will relapse
  • they looked in BALL;;  there are cells resistant to l-aspariginase, dexamethasone, and vincristine
  • a lot of OXPHOS related genes (in DRIs) that may be the genes involved in this resistance
  • it a wonderful note of acknowledgement he dedicated this award to all of his past and present trainees who were the ones, as he said, made this field into what it is and for taking it into directions none of them could forsee

Monday, June 22

1:30 PM – 3:30 PM EDT

Virtual Educational Session

Experimental and Molecular Therapeutics, Drug Development, Cancer Chemistry

Chemistry to the Clinic: Part 1: Lead Optimization Case Studies in Cancer Drug Discovery

How can one continue to deliver innovative medicines to patients when biological targets are becoming ever scarcer and less amenable to therapeutic intervention? Are there sound strategies in place that can clear the path to targets previously considered “undruggable”? Recent advances in lead finding methods and novel technologies such as covalent screening and targeted protein degradation have enriched the toolbox at the disposal of drug discovery scientists to expand the druggable ta

Stefan N Gradl, Elena S Koltun, Scott D Edmondson, Matthew A. Marx, Joachim Rudolph

DETAILS

Monday, June 22

1:30 PM – 3:30 PM EDT

Virtual Educational Session

Bioinformatics and Systems Biology, Molecular and Cellular Biology/Genetics

Informatics Technologies for Cancer Research

Cancer researchers are faced with a deluge of high-throughput data. Using these data to advance understanding of cancer biology and improve clinical outcomes increasingly requires effective use of computational and informatics tools. This session will introduce informatics resources that support the data management, analysis, visualization, and interpretation. The primary focus will be on high-throughput genomic data and imaging data. Participants will be introduced to fundamental concepts

Rachel Karchin, Daniel Marcus, Andriy Fedorov, Obi Lee Griffith

DETAILS

  • Variant analysis is the big bottleneck, especially interpretation of variants
  • CIVIC resource is a network for curation, interpretation of genetic variants
  • CIVIC curators go through multiple rounds of editors review
  • gene summaries, variant summaries
  • curation follows ACSME guidelines
  • evidences are accumulated, categories by various ontologies and is the heart of the reports
  • as this is a network of curators the knowledgebase expands
  • CIVIC is linked to multiple external informatic, clinical, and genetic databases
  • they have curated 7017 clinical interpretations, 2527 variants, using 2578 papers, and over 1000 curators
  • they are currently integrating with COSMIC ClinVar, and UniProt
  • they are partnering with ClinGen to expand network of curators and their curation effort
  • CIVIC uses a Python interface; available on website

https://civicdb.org/home

The Precision Medicine Revolution

Precision medicine refers to the use of prevention and treatment strategies that are tailored to the unique features of each individual and their disease. In the context of cancer this might involve the identification of specific mutations shown to predict response to a targeted therapy. The biomedical literature describing these associations is large and growing rapidly. Currently these interpretations exist largely in private or encumbered databases resulting in extensive repetition of effort.

CIViC’s Role in Precision Medicine

Realizing precision medicine will require this information to be centralized, debated and interpreted for application in the clinic. CIViC is an open access, open source, community-driven web resource for Clinical Interpretation of Variants in Cancer. Our goal is to enable precision medicine by providing an educational forum for dissemination of knowledge and active discussion of the clinical significance of cancer genome alterations. For more details refer to the 2017 CIViC publication in Nature Genetics.

U24 funding announced: We are excited to announce that the Informatics Technology for Cancer Research (ICTR) program of the National Cancer Institute (NCI) has awarded funding to the CIViC team! Starting this year, a five-year, $3.7 million U24 award (CA237719), will support CIViC to develop Standardized and Genome-Wide Clinical Interpretation of Complex Genotypes for Cancer Precision Medicine.

Informatics tools for high-throughput analysis of cancer mutations

Rachel Karchin
  • CRAVAT is a platform to determine, categorize, and curate cancer mutations and cancer related variants
  • adding new tools used to be hard but having an open architecture allows for modular growth and easy integration of other tools
  • so they are actively making an open network using social media

Towards FAIR data in cancer imaging research

Andriy Fedorov, PhD

Towards the FAIR principles

While LOD has had some uptake across the web, the number of databases using this protocol compared to the other technologies is still modest. But whether or not we use LOD, we do need to ensure that databases are designed specifically for the web and for reuse by humans and machines. To provide guidance for creating such databases independent of the technology used, the FAIR principles were issued through FORCE11: the Future of Research Communications and e-Scholarship. The FAIR principles put forth characteristics that contemporary data resources, tools, vocabularies and infrastructures should exhibit to assist discovery and reuse by third-parties through the web. Wilkinson et al.,2016. FAIR stands for: Findable, Accessible, Interoperable and Re-usable. The definition of FAIR is provided in Table 1:

Number Principle
F Findable
F1 (meta)data are assigned a globally unique and persistent identifier
F2 data are described with rich metadata
F3 metadata clearly and explicitly include the identifier of the data it describes
F4 (meta)data are registered or indexed in a searchable resource
A Accessible
A1 (meta)data are retrievable by their identifier using a standardized communications protocol
A1.1 the protocol is open, free, and universally implementable
A1.2 the protocol allows for an authentication and authorization procedure, where necessary
A2 metadata are accessible, even when the data are no longer available
I Interoperable
I1 (meta)data use a formal, accessible, shared, and broadly applicable language for knowledge representation.
I2 (meta)data use vocabularies that follow FAIR principles
I3 (meta)data include qualified references to other (meta)data
R Reusable
R1 meta(data) are richly described with a plurality of accurate and relevant attributes
R1.1 (meta)data are released with a clear and accessible data usage license
R1.2 (meta)data are associated with detailed provenance
R1.3 (meta)data meet domain-relevant community standards

A detailed explanation of each of these is included in the Wilkinson et al., 2016 article, and the Dutch Techcenter for Life Sciences has a set of excellent tutorials, so we won’t go into too much detail here.

  • for outside vendors to access their data, vendors would need a signed Material Transfer Agreement but NCI had formulated a framework to facilitate sharing of data using a DIACOM standard for imaging data

Monday, June 22

1:30 PM – 3:01 PM EDT

Virtual Educational Session

Experimental and Molecular Therapeutics, Cancer Chemistry, Drug Development, Immunology

Engineering and Physical Sciences Approaches in Cancer Research, Diagnosis, and Therapy

The engineering and physical science disciplines have been increasingly involved in the development of new approaches to investigate, diagnose, and treat cancer. This session will address many of these efforts, including therapeutic methods such as improvements in drug delivery/targeting, new drugs and devices to effect immunomodulation and to synergize with immunotherapies, and intraoperative probes to improve surgical interventions. Imaging technologies and probes, sensors, and bioma

Claudia Fischbach, Ronit Satchi-Fainaro, Daniel A Heller

DETAILS

Monday, June 22

1:30 PM – 3:30 PM EDT

Virtual Educational Session

Survivorship

Exceptional Responders and Long-Term Survivors

How should we think about exceptional and super responders to cancer therapy? What biologic insights might ensue from considering these cases? What are ways in which considering super responders may lead to misleading conclusions? What are the pros and cons of the quest to locate exceptional and super responders?

Alice P Chen, Vinay K Prasad, Celeste Leigh Pearce

DETAILS

Monday, June 22

1:30 PM – 3:30 PM EDT

Virtual Educational Session

Tumor Biology, Immunology

Exploiting Metabolic Vulnerabilities in Cancer

The reprogramming of cellular metabolism is a hallmark feature observed across cancers. Contemporary research in this area has led to the discovery of tumor-specific metabolic mechanisms and illustrated ways that these can serve as selective, exploitable vulnerabilities. In this session, four international experts in tumor metabolism will discuss new findings concerning the rewiring of metabolic programs in cancer that support metabolic fitness, biosynthesis, redox balance, and the reg

Costas Andreas Lyssiotis, Gina M DeNicola, Ayelet Erez, Oliver Maddocks

DETAILS

Monday, June 22

1:30 PM – 3:30 PM EDT

Virtual Educational Session

Other Articles on this Open Access  Online Journal on Cancer Conferences and Conference Coverage in Real Time Include

Press Coverage

Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Symposium: New Drugs on the Horizon Part 3 12:30-1:25 PM

Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Session on NCI Activities: COVID-19 and Cancer Research 5:20 PM

Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Session on Evaluating Cancer Genomics from Normal Tissues Through Metastatic Disease 3:50 PM

Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Session on Novel Targets and Therapies 2:35 PM

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The Journey of Antibiotic Discovery

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

The term ‘antibiotic’ was introduced by Selman Waksman as any small molecule, produced by a microbe, with antagonistic properties on the growth of other microbes. An antibiotic interferes with bacterial survival via a specific mode of action but more importantly, at therapeutic concentrations, it is sufficiently potent to be effective against infection and simultaneously presents minimal toxicity. Infectious diseases have been a challenge throughout the ages. From 1347 to 1350, approximately one-third of Europe’s population perished to Bubonic plague. Advances in sanitary and hygienic conditions sufficed to control further plague outbreaks. However, these persisted as a recurrent public health issue. Likewise, infectious diseases in general remained the leading cause of death up to the early 1900s. The mortality rate shrunk after the commercialization of antibiotics, which given their impact on the fate of mankind, were regarded as a ‘medical miracle’. Moreover, the non-therapeutic application of antibiotics has also greatly affected humanity, for instance those used as livestock growth promoters to increase food production after World War II.

 

Currently, more than 2 million North Americans acquire infections associated with antibiotic resistance every year, resulting in 23,000 deaths. In Europe, nearly 700 thousand cases of antibiotic-resistant infections directly develop into over 33,000 deaths yearly, with an estimated cost over €1.5 billion. Despite a 36% increase in human use of antibiotics from 2000 to 2010, approximately 20% of deaths worldwide are related to infectious diseases today. Future perspectives are no brighter, for instance, a government commissioned study in the United Kingdom estimated 10 million deaths per year from antibiotic resistant infections by 2050.

 

The increase in antibiotic-resistant bacteria, alongside the alarmingly low rate of newly approved antibiotics for clinical usage, we are on the verge of not having effective treatments for many common infectious diseases. Historically, antibiotic discovery has been crucial in outpacing resistance and success is closely related to systematic procedures – platforms – that have catalyzed the antibiotic golden age, namely the Waksman platform, followed by the platforms of semi-synthesis and fully synthetic antibiotics. Said platforms resulted in the major antibiotic classes: aminoglycosides, amphenicols, ansamycins, beta-lactams, lipopeptides, diaminopyrimidines, fosfomycins, imidazoles, macrolides, oxazolidinones, streptogramins, polymyxins, sulphonamides, glycopeptides, quinolones and tetracyclines.

 

The increase in drug-resistant pathogens is a consequence of multiple factors, including but not limited to high rates of antimicrobial prescriptions, antibiotic mismanagement in the form of self-medication or interruption of therapy, and large-scale antibiotic use as growth promotors in livestock farming. For example, 60% of the antibiotics sold to the USA food industry are also used as therapeutics in humans. To further complicate matters, it is estimated that $200 million is required for a molecule to reach commercialization, with the risk of antimicrobial resistance rapidly developing, crippling its clinical application, or on the opposing end, a new antibiotic might be so effective it is only used as a last resort therapeutic, thus not widely commercialized.

 

Besides a more efficient management of antibiotic use, there is a pressing need for new platforms capable of consistently and efficiently delivering new lead substances, which should attend their precursors impressively low rates of success, in today’s increasing drug resistance scenario. Antibiotic Discovery Platforms are aiming to screen large libraries, for instance the reservoir of untapped natural products, which is likely the next antibiotic ‘gold mine’. There is a void between phenotanypic screening (high-throughput) and omics-centered assays (high-information), where some mechanistic and molecular information complements antimicrobial activity, without the laborious and extensive application of various omics assays. The increasing need for antibiotics drives the relentless and continuous research on the foreground of antibiotic discovery. This is likely to expand our knowledge on the biological events underlying infectious diseases and, hopefully, result in better therapeutics that can swing the war on infectious diseases back in our favor.

 

During the genomics era came the target-based platform, mostly considered a failure due to limitations in translating drugs to the clinic. Therefore, cell-based platforms were re-instituted, and are still of the utmost importance in the fight against infectious diseases. Although the antibiotic pipeline is still lackluster, especially of new classes and novel mechanisms of action, in the post-genomic era, there is an increasingly large set of information available on microbial metabolism. The translation of such knowledge into novel platforms will hopefully result in the discovery of new and better therapeutics, which can sway the war on infectious diseases back in our favor.

 

References:

 

https://www.mdpi.com/2079-6382/8/2/45/htm

 

https://www.ncbi.nlm.nih.gov/pubmed/19515346

 

https://www.ajicjournal.org/article/S0196-6553(11)00184-2/fulltext

 

https://www.ncbi.nlm.nih.gov/pubmed/21700626

 

http://www.med.or.jp/english/journal/pdf/2009_02/103_108.pdf

 

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Celiac Disease Breakthrough: (1) 472 genes regulated differently in organoids reflecting celiac disease than in non-celiac control organoids (2) bio-products derived from gut microorganisms can be employed to modify the epithelial response to gluten, a finding that could lead to future treatment strategies.

 

Reporter: Aviva Lev-Ari, PhD, RN

“These results confirm our hypothesis that genes and exposure to gluten are necessary but not sufficient, since changes in both the composition and function of the gut microbiome are also needed to switch from genetic predisposition to clinical outcome, as shown by our data,” said Alessio Fasano, HMS professor of pediatrics at Mass General, director of MIBRC and co-senior author of the paper.

https://hms.harvard.edu/news/major-shift?utm_source=Silverpop&utm_medium=email&utm_term=field_news_item_3&utm_content=HMNews05132019

 

 

Image Source: iStock/wildpixel

Article OPEN Published: 

Human gut derived-organoids provide model to study gluten response and effects of microbiota-derived molecules in celiac disease

Scientific Reports volume 9, Article number: 7029 (2019Download Citation

Abstract

Celiac disease (CD) is an immune-mediated disorder triggered by gluten exposure. The contribution of the adaptive immune response to CD pathogenesis has been extensively studied, but the absence of valid experimental models has hampered our understanding of the early steps leading to loss of gluten tolerance. Using intestinal organoids developed from duodenal biopsies from both non-celiac (NC) and celiac (CD) patients, we explored the contribution of gut epithelium to CD pathogenesis and the role of microbiota-derived molecules in modulating the epithelium’s response to gluten. When compared to NC, RNA sequencing of CD organoids revealed significantly altered expression of genes associated with gut barrier, innate immune response, and stem cell functions. Monolayers derived from CD organoids exposed to gliadin showed increased intestinal permeability and enhanced secretion of pro-inflammatory cytokines compared to NC controls. Microbiota-derived bioproducts butyrate, lactate, and polysaccharide A improved barrier function and reduced gliadin-induced cytokine secretion. We concluded that: (1) patient-derived organoids faithfully express established and newly identified molecular signatures characteristic of CD. (2) microbiota-derived bioproducts can be used to modulate the epithelial response to gluten. Finally, we validated the use of patient-derived organoids monolayers as a novel tool for the study of CD.

Mass. General researchers develop 3D “mini-gut” model to study autoimmune response to gluten in celiac and non-celiac patient tissue

Gene expression of intestinal organoids reflects functional differences found in celiac disease

In pursuit of a novel tool for the research and treatment of celiac disease, scientists at the Mucosal Immunology and Biology Research Center (MIBRC) at Massachusetts General Hospital (MGH) have validated the use of intestinal organoids. These three-dimensional tissue cultures are miniature, simplified versions of the intestine produced in vitro. Taking tissue from duodenal biopsies of celiac and non-celiac patients, researchers created the “mini-guts” to explore how the gut epithelium and microbiota-derived molecules respond to gluten, a complex class of proteins found in wheat and other grains.

“We currently have no animal model that can recapitulate the response to gluten that we see in humans,” says Stefania Senger, PhD, co-senior author of the study published in Scientific Reports this week. “Using this human tissue model, we observed that intestinal organoids express the same molecular markers as actual epithelium in the celiac tissue, and the signature gene expression reflects the functional differences that occur when epithelia of celiac disease patients are exposed to gliadin.” Gliadin and glutenin proteins are main components of gluten.

Celiac disease is triggered when genetically predisposed individuals consume gluten. The condition affects approximately 1 percent of the U.S. population. Based on current data, the onset of celiac disease is thought to be preceded by the release of the protein zonulin, which is triggered by the activation of undigested gliadin to induce an autoimmune response. This leads to increased intestinal permeability and a disrupted barrier function. Novel evidence suggests that the microorganisms in the gastrointestinal tract may play a role in the onset of celiac disease.

Earlier studies from the MIBRC group and others have shown that human organoids “retain a gene expression that recapitulates the expression of the tissue of origin, including a diseased state,” the authors write. Through RNA sequencing, the new findings validate the organoid model as a “faithful in vitro model for celiac disease,” Senger says.
Using whole-transcriptome analysis, the researchers identified 472 genes regulated differently in organoids reflecting celiac disease than in non-celiac control organoids. These included novel genes associated with epithelial functions related to the pathogenesis of celiac disease – including gut barrier maintenance, stem cell regeneration and innate immune response. A second finding of the study shows that bioproducts derived from gut microorganisms can be employed to modify the epithelial response to gluten, a finding that could lead to future treatment strategies.

“These results confirm our hypothesis that genes and exposure to gluten are necessary but not sufficient, since changes in both the composition and function of the gut microbiome are also needed to switch from genetic predisposition to clinical outcome, as shown by our data,” says Alessio Fasano, MD, director of the Mucosal Immunology and Biology Research Center and co-senior author.

Senger adds, “We believe our observations represent a major shift in the study of celiac disease. We are confident that with adequate funding we could achieve major goals that include the development and implementation of high-throughput drug screenings to quickly identify new treatments for patients and expand the organoid repository to develop more complex models and pursue personalized treatment.”
Additional co-authors of the paper are first author Rachel Freire, PhD, along with Laura Ingano and Gloria Serena, PhD, of the MGH MIBRC; Murat Cetinbas, PhD, and Ruslan Sadreyev, PhD, MGH Department of Molecular Biology; Anthony Anselmo, PhD, formerly of MGH Molecular Biology and now with PatientsLikeMe, Cambridge, Mass.; and Anna Sapone, MD, PhD, Takeda Pharmaceuticals International. Support for the study includes National Institutes of Health grants RO1 DK104344-01A1 and 1U19 AI082655-02 and the Egan Family Foundation.

SOURCE

https://www.massgeneral.org/about/pressrelease.aspx?id=2403

 

Other related articles and e-Books by LPBI Group’s Authors published on this Open Access Online Scientific Journal include the following:

 

Series D: e-Books on BioMedicine – Metabolomics, Immunology, Infectious Diseases

  • Metabolomics 

VOLUME 1: Metabolic Genomics and Pharmaceutics. On Amazon.com since 7/21/2015

http://www.amazon.com/dp/B012BB0ZF0

Gluten-free Diets

Writer and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2015/03/01/gluten-free-diets/

 

Breakthrough Digestive Disorders Research: Conditions affecting the Gastrointestinal Tract.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/12/12/breakthrough-digestive-disorders-research-conditions-affecting-the-gastrointestinal-tract/

 

Collagen-binding Molecular Chaperone HSP47: Role in Intestinal Fibrosis – colonic epithelial cells and subepithelial myofibroblasts

Curators: Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/01/25/collagen-binding-molecular-chaperone-hsp47-role-in-intestinal-fibrosis-colonic-epithelial-cells-and-subepithelial-myofibroblasts/

Expanding area of Tolerance-inducing Autoimmune Disease Therapeutics: Key Players

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/01/17/expanding-area-of-tolerance-inducing-autoimmune-disease-therapeutics-key-players/

 

What is the key method to harness Inflammation to close the doors for many complex diseases?

Author and Curator: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/03/21/what-is-the-key-method-to-harness-inflammation-to-close-the-doors-for-many-complex-diseases/

Read Full Post »

The second annual PureTech Health BIG (Brain-Immune-Gut) Summit 2019 – By invitation only –

Selected Tweets from  #BIGAxisSummit

by @pharma_BI @AVIVA1950

for @pharmaceuticalintelligence.com

Reporter: Aviva Lev-Ari, PhD, RN

 

January 30 – February 1, 2019

The second annual PureTech Health BIG Summit brings together an elite ensemble of leading scientific researchers, investors, and CEOs and R&D leaders from major pharmaceutical, technology, and biotech companies.

The BIG Summit is designed to stimulate ideas that will have an impact on existing pipelines and catalyze future interactions among a group of delegates that represent leaders and innovators in their fields.

Please follow the discussion on Twitter using #BIGAxisSummit

By invitation only; registration is non-transferable.

For more information, please contact PureTechHealthSummit@PureTechHealth.com

 

HOST COMMITTEE

Participants

 

BIG SUMMIT AGENDA

(Subject to Change)

PureTech Health BIG Summit 2019 Agenda_FINALv2_WEBSITE.jpg

“Almost starting to understand immunology at this thought-provoking @PureTechh #BIGAxisSummit. Great Speakers.”

-tweet by Simone Fishburn, BioCentury @SimoneFishburn

SOURCE

https://bigsummit2019.com/agenda/

 

Selected Tweets from  #BIGAxisSummit

by @pharma_BI @AVIVA1950

for @pharmaceuticalintelligence.com

Gail S. Thornton Selections

Luke Timmerman‏ @ldtimmerman 7h7 hours ago

Back for final sessions at #BIGAxisSummit. @PureTechH Jim Harper of Sonde Health talking about how voice data — pacing, fine motor articulation, oscillation — can point the way to objective, quantitative measures for detecting and monitoring depression.

 

Eddie Martucci

 @EddieMartucci 5h5 hours ago

Paul Biondi at #BIGAxisSummit : What makes big deals happen is financial, and *deep conviction* of a big future fit. Disproportionate valuation from bidders is expected.

Love this. We often reduce everything to mathematical analyses to champion or ridicule deals. Not that simple

 

PureTech Health Plc‏ @PureTechH Jan 31

Bob Langer (@MIT) asks how #lymphatics affected by #aging. Santambrogio: typically blame aging #immune cells for increased disease, but aging affects lymphatics too (less efficient trafficking shown). Rejuvenating these could affect several aging-related diseases #BigAxisSummit

 

PureTech Health Plc‏ @PureTechH Jan 31

Viviane Labrie (@VAInstitute) discusses why the appendix has been identified as a potential starting point for #parkinsons #BIGAxisSummit

 

PureTech Health Plc‏ @PureTechH Jan 31

Chris Porter (@MIPS_Australia) notes #lymphatics is major route for trafficking #immune cells that surveil gut and respond to immune & #autoimmune stimuli. This is key in #BIGAxis interactions and why lymphatics-targeted therapies could enhance #immunomodulation #BIGAxisSummit

 

Dr. Stephen J. Williams Selections

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4.

5.

Dr. Irina Robu Selection

1.

2.

3.

4.

5.

Dr. Sudipta Saha Selection

1.

2.

3.

4.

5.

 

 

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Ability of gut microbiota to influence the bioavailability of in Parkinson’s disease – The presence of more bacteria producing the tyrosine decarboxylase (TDC) enzyme means less levodopa in the bloodstream

 

Reporter: Aviva Lev-Ari, PhD, RN

 

Decarboxylase enzymes can convert levodopa into dopamine. In contrast to levodopa, dopamine cannot cross the , so patients are also given a decarboxylase inhibitor. “But the levels of levodopa that will reach the brain vary strongly among Parkinson’s disease patients.

The bacterial  decarboxylase enzyme, which normally converts tyrosine into tyramine, but was found to also convert levodopa into . “We then determined that the source of this decarboxylase was Enterococcus bacteria.” The researchers also showed that the conversion of levodopa was not inhibited by a high concentration of the amino acid tyrosine, the main substrate of the bacterial tyrosine decarboxylase enzyme.

  • Carbidopa is over 10,000 times more potent in inhibiting the human decarboxylase,
  • the higher abundance of bacterial enzyme in the small intestines of rats reduced levels of levodopa in the bloodstream,
  • positive correlation between disease duration and levels of bacterial tyrosine decarboxylase.
  • Some Parkinson’s disease patients develop an overgrowth of small intestinal bacteria including Enterococci due to frequent uptake of proton pump inhibitors, which they use to treat gastrointestinal symptoms associated with the disease.
  • Altogether, these factors result in a vicious circle leading to an increased levodopa/decarboxylase inhibitor dosage requirement in a subset of patients.El Aidy concludes that
  • the presence of the bacterial tyrosine decarboxylase enzyme can explain why some patients need more frequent dosages of levodopa to treat their motor fluctuations. “This is considered to be a problem for Parkinson’s disease patients, because a higher dose will result in dyskinesia, one of the major side effects of levodopa treatment.

SOURCE

https://www.rdmag.com/news/2019/01/how-gut-bacteria-affect-treatment-parkinsons-disease?type=cta&et_cid=6585419&et_rid=461755519&linkid=Mobius_Link

Article OPEN Published: 

Gut bacterial tyrosine decarboxylases restrict levels of levodopa in the treatment of Parkinson’s disease

Nature Communications volume 10, Article number: 310 (2019) Download Citation

Abstract

Human gut microbiota senses its environment and responds by releasing metabolites, some of which are key regulators of human health and disease. In this study, we characterize gut-associated bacteria in their ability to decarboxylate levodopa to dopamine via tyrosine decarboxylases. Bacterial tyrosine decarboxylases efficiently convert levodopa to dopamine, even in the presence of tyrosine, a competitive substrate, or inhibitors of human decarboxylase. In situ levels of levodopa are compromised by high abundance of gut bacterial tyrosine decarboxylase in patients with Parkinson’s disease. Finally, the higher relative abundance of bacterial tyrosine decarboxylases at the site of levodopa absorption, proximal small intestine, had a significant impact on levels of levodopa in the plasma of rats. Our results highlight the role of microbial metabolism in drug availability, and specifically, that abundance of bacterial tyrosine decarboxylase in the proximal small intestine can explain the increased dosage regimen of levodopa treatment in Parkinson’s disease patients.

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