Delivering Medicine Beyond Culture and Disciplines

Plenary Lectures

  • Dr Alex R Cook
  • Dr Alex R Cook
    Saw Swee Hock School of Public Health, National University of Singapore, Singapore

Evaluating border policies for COVID-19 spread

Dr Alex Cook is an Associate Professor at the NUS Saw Swee Hock School of Public Health where he is also the Vice Dean (Research). He works on infectious disease modelling and statistics, including dengue, influenza and other respiratory pathogens, and on population modelling to assess the effect of evolving demographics ..... READ MOREon non-communicable diseases such as diabetes. His multidisciplinary team brings together researchers from the fields of statistics, computational biology, computer engineering, mathematics, geography and environmental sciences.

Abstract

International travel restrictions were one of the first and longest lasting policies implemented to control the pandemic, yet a hodge podge of different regimes exist internationally. As countries—with the glaring exception of China—have begun reopening their borders to travel, it is on of import to determine which specific measures to retain, and for travellers from which countries. In the middle of 2020, we developed a computer simulation model to assess the impact of different combinations of testing and quarantine on the number of infected travellers who would be reach the receiving population, undiagnosed, and the expected number of secondary cases they would cause there. In this presentation I will discuss the genesis of the model, some technical details, and how it has been applied and ‘marketed’ to policy makers.

  • Professor Hans C Clevers
  • Professor Hans C Clevers
    University Medical Center Utrecht, Utrecht, Netherlands | University of Utrecht, Netherlands
    Hubrecht Institute of the Royal Netherlands Academy of Arts, Utrecht, Netherlands
    Princess Maxima Center for Pediatric Oncology, Utrecht, Netherlands

Stem Cell-based Organoids in Human Disease

Hans Clevers obtained his MD degree in 1984 and his PhD degree in 1985 from the University Utrecht, the Netherlands. His postdoctoral work (1986-1989) was done with Cox Terhorst at the Dana-Farber Cancer Institute of the Harvard University, Boston, USA. ..... READ MORE

From 1991-2002 Hans Clevers was Professor in Immunology at the University Utrecht and, since 2002, Professor in Molecular Genetics. From 2002-2012 he was director of the Hubrecht Institute in Utrecht. From 2012-2015 he was President of the Royal Netherlands Academy of Arts and Sciences (KNAW). From 2015 - June 2019 he was Director Research of the Princess Maxima Center for pediatric oncology. He continues to run his lab in the Hubrecht Institute.

Throughout his career, he has worked on the role of Wnt signalling in stem cells and cancer. His discoveries include TCF as the nuclear Wnt effector, the role of Wnt in adult stem cell biology and of Wnt pathway mutations in colon cancer, Lgr5 as a marker of multiple novel types of adult stem cells and as receptor for the Wnt-amplifying R-spondins, and –finally- a method to grow ever-expanding mini-organs (‘organoids’) from Lgr5 stem cells derived from a range of healthy or diseased human tissues. This has led to over 750 publications and >90,000 citations.

Hans Clevers is member of the Royal Netherlands Academy of Arts and Sciences (2000), of the American Academy of Arts and Sciences (2012) and the National Academy of Sciences of the USA (2014), the Academie des Sciences (2016) and the Orden pour le Merite der Wisschschaften und Kuenste (2017).

He is the recipient of multiple awards, including the Dutch Spinoza Award in 2001, the Swiss Louis Jeantet Prize in 2004, the German Meyenburg Cancer Research Award in 2008, the German Ernst Jung-Preis für Medizin in 2011, the French Association pour la Recherche sur le Cancer (ARC) Léopold Griffuel Prize, the Heineken Prize (2012), the Breakthrough Prize in Life Sciences (2013), the 2015 ISSCR McEwen Award for Innovation and the Academy Professor Prize (2015), and the Körber European Science Prize (2016).

He is Chevalier de la Legion d’Honneur since 2005, Knight in the Order of the Netherlands Lion since 2012 and German prize.

Abstract

Stem cells are the foundation of all mammalian life. Stem cells build and maintain our bodies throughout life. Two types of stem cells are discerned.

1) Embryonic stem cells (ES cells) are briefly present in the early human or mouse embryo, a few days after fertilization. These ES cells can be grown indefinitely in the lab and have the potential to build each and every tissue in our body. Because of this ‘pluripotency’, ES cells hold great promise for therapeutic application in the field of regenerative medicine. It is also possible to take skin cells (or other cells) from adults and convert these in the lab into cells with ES properties, so called iPS cells. Many of the hurdles that ES cell technology have faced, do not exist for iPS cells.

2) Adult stem cells. Every organ in our body is believed to harbor its own dedicated stem cells. These adult stem cells replace tissue that is lost due to wear and tear, trauma and disease. Adult stem cells are highly specialized and can only produce the tissue in which they reside; they are ‘multipotent’. Examples are bone marrow stem cells that make all blood cells, skin stem cells and gut stem cells. Even the brain is now known to harbor its specialized stem cells. The adult stem cells allow us to live 80-90 years, but this comes at a cost: they are the cells that most easily transform into cancer cells.

Both types of stem cells can be used to establish ‘organoids’, 3D structures established in a dish, that recapitulate many aspects of the organ they represent. Pluripotent stem cells can be taken through the developmental steps that establish organs during embryogenesis. This has worked particularly well for parts of the the central nervous system, the kidney and GI organs. We have shown that adult epithelial stem cells carrying the generic Lgr5 marker can be cultured under tissue-repair conditions and generate epithelial organoids directly from healthy and diseased organs such as the gut, the liver, the lung and the pancreas. Organoid technology opens a range of avenues for the study of development, physiology and disease, for drug development and for personalized medicine. In the long run, cultured mini-organs may replace transplant organs from donors and hold promise in gene therapy.

  • Professor Michel WJ Sadelain
  • Professor Michel WJ Sadelain
    Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, USA

From T cell engineering to CAR therapy: the emergence of living drugs

Michel Sadelain, MD, PhD, is the Director of the Center for Cell Engineering and the incumbent of the Stephen and Barbara Friedman Chair at Memorial Sloan-Kettering Cancer Center. He is a Member of the Immunology Program and the Departments of Medicine and Pediatrics. ..... READ MORE

Dr. Sadelain’s research focuses on human cell engineering and cell therapy to treat cancer and hereditary blood disorders. His laboratory has made several seminal contributions to the field of chimeric antigen receptors (CARs), from their conceptualization and optimization to their clinical translation for cancer immunotherapy. His group was the first to publish dramatic molecular remissions in patients with chemorefractory acute lymphoblastic leukemia following treatment with autologous CD19-targeted T cells.

Dr. Sadelain is the recipient of the Cancer Research Institute’s Coley Award for Distinguished Research in Tumor Immunology, the Sultan Bin Khalifa International Award for Innovative Medical Research on Thalassemia, the NYPLA Inventor of the Year award, the Passano award, the Pasteur-Weizmann award, the Gabbay award, the INSERM International Prize Laureate, the Laureate of the 48th Foundation ARC Léopold Griffuel and most recently the Outstanding Achievement Award from the American Society of Gene and Cell Therapy. He previously served on the NIH Recombinant DNA Advisory Committee and as President of the American Society for Gene and Cell Therapy.

Abstract

Natural immune responses fall short of eradicating tumors in most cancer patients. The genetic engineering of T cells offers a means to repurpose immune cells to perform enhanced therapeutic functions. The first successful embodiment of such engineered immunity is chimeric antigen receptor (CAR) therapy targeting CD19. CARs are synthetic receptors that redirect and reprogram T cells to mediate tumor rejection. We demonstrated over two decades ago that combining signaling motifs in these artificial receptors for enabled T cells to not only lyse specified targets but also expand, paving the way for the exploration of “living drugs”.

CARs that target CD19, a cell surface molecule found in most leukemias and lymphomas, have produced remarkable responses in patients with refractory, relapsed B cell malignancies. The US FDA approved the first CD19 CAR therapies in 2017. A number of CAR targets are currently under investigation, including BCMA for multiple myeloma and many more. Solid tumors pose additional challenges, including an immunosuppressive microenvironment, restricted access and low-level target expression. We are addressing the latter through combinatorial targeting and the design of antigen-sensitive receptors such as HIT receptors.

The functional persistence of CAR T cells is a fundamental requirement for effective therapy. We have demonstrated that transcriptional regulation of CAR expression, based on CRISPR/Cas9-mediated T cell editing, and optimization of CAR signaling strength, prolong the CAR T cells’ functionality. A complementary approach is to shape the epigenome of engineered T cells, which we have found to be powerful as well. Lastly, we have begun to generate CAR T cells from pluripotent stem cells. These induced T cells, albeit not yet equivalent to natural T cells, are starting to achieve substantial anti-tumor efficacy in preclinical models.