Kristin Baldwin | The Scripps Research Institute, USA
Direct reprogramming of differentiated cells into iPSCs or into other cell lineages through trans-differentiation induces cell fate changes that do not occur normally during the lifetime of an organism. The robustness of these methods is therefore somewhat surprising, suggesting that reprogramming may be accomplished through more diverse mechanisms than previously anticipated. For example, during development, cell fate changes are largely initiated at the membrane, while most reprogramming methods act in the nucleus. To identify cell surface triggers for reprogramming to pluripotency we screened a combinatorial antibody library and identified antibodies that replace transcription factors Sox2 and c-Myc or Oct4 during reprogramming of fibroblasts to iPSCs. These studies offer a potentially safer method to produce iPSCs for therapies and identify antibodies as candidate catalysts for inducing cell fate changes in vivo. Using a smaller libarary of transcription factors, we have also identified ~75 new ways to rapidly convert fibroblasts into neurons of diverse identities. These new precision neuronal reprogramming methods may aid in modeling neurologic disease and guide future efforts to transplant or transdifferentiate neurons in vivo into those with a desired subtype identity.
Dr. Baldwin is a Professor of Neuroscience at the Scripps Research Institute, an Adjunct Associate Professor in the Department of Neuroscience at UCSD and a member of the Sanford Consortium for Regenerative Medicine. Dr. Baldwin’s research interests lie at the intersection of molecular neurobiology, genomics and stem cell biology/reprogramming. Her lab uses cloning and reprogramming to address questions of cellular diversity and genome stability in the mouse brain and in other tissues from humans. After generating the first iPSC cells to produce entire fertile adult mice and developing viral approaches to trace long range neural circuits with single cell resolution, the lab has become increasingly focused on developing reprogramming techniques to produce useful human cell types in vitro to model disease and enable drug screening. Dr. Baldwin received a B.S. in Economics and Zoology from Duke University, a Ph.D. in Immunology at Stanford University and performed postdoctoral work in neurobiology with Dr. Richard Axel at Columbia University. She has been named Pew Scholar in Biomedical Research, a Donald E. and Delia B. Baxter Foundation Faculty Scholar, a Kavli Fellow and most recently received an NIH Director’s Pioneer Award.
René Bernards | Netherlands Cancer Institute (NKI), Netherlands
To find optimal combinations of targeted cancer drugs, synthetic lethality screens can help to guide the choice of drugs. As one example, my laboratory has found, through a synthetic lethality genetic screen, that co-inhibition of both BRAF and EGFR in BRAF mutant colon cancer is very effective. Such a combination is counter-intuitive, given that EGFR functions upstream of oncogenic BRAF in signaling.
In my lecture, I will focus on two new concepts in the treatment of cancer. First, I will discuss how we can identify acquired vulnerabilities of drug-resistant cancers. Based on the notion that every acquired strength (i.e. drug resistance) must have an associated weakness, we have searched for acquired vulnerabilities when BRAF mutant melanomas become resistant to the combination of BRAF and MEK inhibitors. Our pre-clinical findings indicate a major acquired sensitivity of such drug resistant melanomas for HDAC inhibitors. Initial results from a clinical trial in our center confirm our pre-clinical findings.
Second, I will discuss how we can use sequential drug treatment to deliver a “one-two punch” lethal blow to cancer cells. In this scenario, we use the first drug to expose a major new vulnerability of the cancer cells that is subsequently targeted by the second drug. Examples of effective sequential drug treatments based on the induction of senescence in liver cancer followed by killing of senescent cells with a senolytic agent will be presented.
René Bernards is a professor of molecular carcinogenesis at the Netherlands Cancer Institute. His laboratory uses functional genomic approaches to find vulnerabilities of cancers that can be exploited therapeutically. Using the concept of synthetic lethality, his laboratory searches for combinations of drugs that are lethal for cancer cells and for vulnerabilities of cancer cells of a defined genotype. Amongst his honors are the Pezcoller Foundation-FECS Recognition for Contribution to Oncology, the Ernst W. Bertner Award for Cancer Research from the M.D. Anderson Cancer Center, the ESMO Lifetime Achievement Award in Translational Research in Breast Cancer. He is also a member of the Royal Netherlands Academy of Sciences.
Mina J. Bissell | Lawrence Berkeley National Laboratory, USA
It should be clear by now that cancer is a tissue- and organ-specific disease. Thus to understand a given malignancy, we could do well to know the biology of the normal tissue and the organ from which the malignant tumors develop.
To understand initiation of breast tumors, one must consider the health of the entire organ within the context of the individual: the age of the individual and the medical condition, not only the cells that become, or have become, malignant but the entire tissue and the microenvironment of the cells that have been targeted to become tumors.
I will discuss three fundamental questions: 1) How do epithelial cells know to stop growing and why malignant cells don’t? 2) What is the basis of tissue- and organ- specificity? And 3) how physical and biochemical signals help make a tissue?
We have shown that unless the architecture of the tissue is severely compromised, the cells will not become malignant or invade. Indeed we can revert the malignant cells to ‘normal phenotype’ despite myriads of mutations, deletions and amplifications if we restore the architecture. We now have discovered new pathways that regulate growth and quiescence in human breast cells(1), an intricate mechanism by which the ECM and cytoskeletal connections may interact with nucleus and chromatin(2), and how the morphogenetic signaling loop in breast epithelial tissue is maintained.(3)?
This is a tale of how form and function integrate: From laminins to lamins, P53, HOX D10 and back to laminins. See you there!
1) Cell Report, 2017
2) J. Cell Science, 2017
3) E.Life (in Press)
Mina J. Bissell is Distinguished Scientist, the highest rank bestowed at Lawrence Berkeley National Laboratory (LBNL) and serves as Senior Advisor to the Laboratory Director on Biology. She is also Faculty of four Graduate Groups in UC Berkeley: Comparative Biochemistry, Endocrinology, Molecular Toxicology, and Bioengineering (UCSF/UCB joint program). Having challenged several established paradigms, Bissell is a pioneer in breast cancer research and her body of work has provided much impetus for the current recognition of the significant role that extracellular matrix (ECM) signaling and microenvironment play in gene expression regulation in both normal and malignant cells. Her laboratory developed novel 3D assays and techniques that demonstrate her signature phrase: after conception, “phenotype is dominant over genotype.”
Bissell earned her doctorate in microbiology and molecular genetics from Harvard Medical School, won an American Cancer Society fellowship for her postdoctoral studies, and soon after joined LBNL. She was the founding Director of the Cell and Molecular Biology Division and later the Associate Laboratory Director for all Life Sciences at Berkeley Lab where she recruited outstanding scientists and developed a strong program in cell and molecular biology and breast cancer.
Bissell has published more than 400 publications and is one of the most sought-after speakers in the field. She has received numerous honors and awards, which include: U.S. Department of Energy’s E.O. Lawrence Award, AACR’s G.H.A. Clowes Memorial Award, the Pezcoller Foundation-AACR International Award, Susan G. Komen Foundation’s Brinker Award, BCRF Foundation’s Jill Rose Award, Berkeley Lab’s inaugural Lifetime Achievement Prize, American Cancer Society’s Medal of Honor, MD Anderson Cancer Center’s highest honor – the Ernst W. Bertner Award, the Honorary Medal from the Signaling Societies in Germany, ASCB’s highest honor – the E.B. Wilson Medal, and the 2017 AACR Award for Lifetime Achievement in Cancer Research. Bissell is an inspiring mentor and in her honor, the University of Porto, Portugal established the Mina J. Bissell Award which is given every three years to a person who has dramatically changed a field. She is the recipient of Honorary Doctorates from both Pierre & Marie Curie University in Paris, France and University of Copenhagen in Denmark. Bissell is not only an elected Fellow of most U.S. honorary scientific academies, including National Academy of Sciences (NAS), National Academy of Medicine (NAM), and American Philosophical Society (APS), but she also sits on many national and international scientific boards and continues to engage in full-time research, among other scientific activities.
Don W. Cleveland | University of California San Diego, USA
The genes whose mutation causes neurodegenerative disease are widely expressed within neurons and non-neurons of the nervous system, producing damage not only within the most vulnerable neurons but also within their partner neurons and glia. Sustained gene silencing or altered pre-mRNA splicing broadly within neurons and non-neurons throughout the nervous system has been achieved using a clinically feasible “designer DNA drug” injection of antisense oligonucleotides into the nervous system. Single dose injection of an ASO has been shown to produce sustained, catalytic (RNase H-dependent) RNA degradation of a target mRNA, thereby producing slowing of disease progression for inherited ALS in rodents or sustained partial disease reversal for Huntington’s-like disease. An ASO that corrects splicing of the SMN2 pre-mRNA has been approved for spinal muscular atrophy (SMA), one of the most abundant childhood inherited diseases. Hexanucleotide expansion in the C9orf72 gene is the most frequent cause of both ALS and frontal temporal dementia. Single dose ASO infusion has been demonstrated to catalyze selective destruction of repeat-containing C9ORF72 RNAs, without targeting mRNAs encoding the C9ORF72 protein. Efficacy of ASOs in lowering expression of tau mRNA has been demonstrated and a clinical trial in Alzheimer’s disease has been initiated. An extension of this approach is development of synthetic CRISPR RNAs to induce transient Cas9 activation to inactivate a target gene.
Dr. Don Cleveland has made field leading contributions in cancer genetics and neurosciences. He is currently Professor and Chair of the Department of Cellular and Molecular Medicine at the University of California at San Diego, as well as a member of the Ludwig Institute for Cancer Research. He has been elected to the U.S. National Academy of Sciences and National Academy of Medicine. He initially identified tau, the protein which accumulates aberrantly in Alzheimer’s disease and which is the protein whose misfolding underlies chronic traumatic brain injury (now receiving international attention from its impact in athletics, especially American football). He uncovered the mechanisms underlying the major genetic forms of Amyotrophic Lateral Sclerosis (ALS) and demonstrated that disease involves neurons and their non-neuronal neighbors. He has developed gene silencing therapy for neurodegenerative diseases using designer DNA “antisense oligonucleotide (ASO)” drugs. Clinical trials with these ASOs have been initiated for multiple neurodegenerative diseases, including for ALS and Huntington’s diseases.
Maike Sander | University of California San Diego, USA
New approaches are being explored aimed at restoring functional beta cell mass as a treatment strategy for diabetes. The approach closest to clinical implementation is the replacement of beta cells with human pluripotent stem cell–derived cells, which are currently under investigation in a clinical trial to assess efficacy and safety in humans. Another intensely pursued strategy is to stimulate the regeneration of beta cells by enhancement of beta cell replication. Recent studies have revealed novel pharmacologic targets for stimulating beta cell replication. Manipulating these targets or the pathways they regulate could be a strategy for promoting the expansion of residual beta cells in diabetic patients. I will provide an overview of progress made toward beta cell replacement and regeneration, highlight contributions from my laboratory to the field, and discuss promises and challenges for clinical implementation of these strategies.
Maike Sander is the Director of the Pediatric Diabetes Research Center and Co-Director of the Center on Diabetes in the Institute of Engineering in Medicine at UC San Diego. Her laboratory has uncovered fundamental mechanisms that underlie the formation and function of insulin-producing pancreatic beta cells, which are affected in diabetes. By defining the impact of environmental cues on cell fate determination and plasticity, her laboratory aims to identify strategies for beta cell regeneration and replacement in order to develop novel treatments for diabetes. Dr. Sander obtained a medical degree from the University of Heidelberg in Germany and held faculty positions at the University of Hamburg, Germany and the University of California, Irvine before moving to the University of California, San Diego in 2008. Dr. Sander is an elected member of the American Society of Clinical Investigation and the German Academy of Sciences (Leopoldina), and a member of the NIH-Human Islet Research Network. She is the recipient of the Grodsky Award from the Juvenile Diabetes Research Foundation and the 2017 Humboldt Research Award.
Jan van Deursen | Mayo Clinic, USA
Cellular senescence has emerged as a potentially important contributor to aging and age-related disease and as an attractive target for therapeutic exploitation. Direct evidence for the deleterious effects of senescence in aging originates from BubR1-progeroid mice in which inactivation of the p16Ink4a senescence pathway or the elimination of p16Ink4a-positive senescent cells dramatically attenuates aging. Using transgenic mouse models that selectively kill p16Ink4a positive cells, we have investigated the role of senescence in health and life span of normal mice, as well as its role in common age-related diseases. The implications of these studies for the design and effectiveness of senotherapies to extend healthy lifespan will be discussed.
Jan M. van Deursen, received his Ph.D. degree in Cell Biology at the University of Nijmegen, Netherlands in 1993. He joined the staff of Mayo Clinic in 1999, where he directs a curiosity-driven research program focused on the basic biology of cancer and aging. Dr. van Deursen also directs of the transgenic and gene knockout core facility (1999-present), the senescence program of the Robert and Arlene Kogod Center on Aging (2009-present), the cell biology program of the comprehensive cancer center (2012-present), the cancer and cell aging platform of the center for biomedical discovery (2015-present), and the Paul Glenn laboratories of senescence (2013-present). Since 2012, he serves as chair of the department of Biochemistry and Molecular Biology.
Erwin Wagner | Spanish National Cancer Research Centre (CNIO), Spain
Our studies aim to analyze gene function in healthy and pathological conditions, e.g. in tumour development, using the mouse as a model organism, but also employing patient-derived samples. Specifically, the functions of the AP-1 (Fos/Jun) transcription factor complex regulating cell proliferation, differentiation and oncogenesis, as well as the cross-talk between organs are being investigated. The goal is to define molecular pathways leading to disease/cancer development and to identify novel therapeutic targets. We focus on elucidating a causal link between inflammation, cancer and AP-1 (Fos/Jun) expression using cell type-specific, switchable genetically engineered mouse models (GEMMs). We are also developing and characterizing new GEMMs for cancer and human diseases, such as for fibrosis and psoriasis.
I will focus in my talk on recent studies towards understanding skin and lung pathologies at the cross-road between chronic inflammation and cancer. A major systemic complication of cancer is Cancer-Associated-Cachexia (CAC), where chronic inflammation, metabolic dysfunction and increased metabolic rate have been described. We showed that a phenotypic switch from white adipose tissue (WAT) to brown fat, termed WAT browning, takes place at the initial stages of CAC, before skeletal muscle atrophy. Recent results suggest that liver metabolism, the immune system and endocrine organs are dysregulated in CAC, which will also be discussed.
Erwin Wagner obtained his PhD in 1978 for his studies on bacterial genetics at the Max-Planck Institute in Berlin. He did his postdoctoral training with Beatrice Mintz in Philadelphia (1979-83), became a Group Leader at the EMBL in Heidelberg (1983-88) and from 1988 he was Senior Scientist and Deputy Director at the IMP in Vienna, Austria. In 2008 he became Vice Director (2008-11) and Director of the Cancer Cell Biology Program at the CNIO in Madrid. His work focuses on understanding gene functions in mammalian development and disease/cancer, employing genetic mouse models for human diseases. His work has a strong focus on defining the functions of the AP-1(Fos/Jun) transcription factor complex in inflammation, metabolism and cancer.
Marius Wernig | Stanford University, USA
Cellular differentiation and lineage commitment are considered robust and irreversible processes during development. Challenging this view, we found that expression of only three neural lineage-specific transcription factors Ascl1, Myt1l, and Brn2 could directly convert mouse fibroblasts into functional in vitro. These induced neuronal (iN) cells expressed multiple neuron-specific proteins, generated action potentials, and formed functional synapses. Thus, iN cells are bona fide functional neurons.
Unlike reprogramming towards other lineages such as iPS cell reprogramming, the iN cell reprogramming process is very efficient (up to 20%) and deterministic. We previously found a molecular explanation in that Ascl1, a transcriptional activator, can access its physiological targets in fibroblasts even though these sites are in a closed chromatin state, thus robustly inducing a neuronal transcriptional program and rearranging the local chromatin. Surprisingly, Ascl1 alone is sufficient to induce fully functional iN cells, but in the majority of cells activates also non-neuronal programs. We further show, that Myt1l, a zinc finger domain protein, primarily functions as transcriptional repressor suppressing the fibroblast and other non-neuronal programs. This suggests that the physiological role of Myt1l is to ensure maintenance of neuronal identity by repressing many transcriptional program except neuronal genes, thereby functioning in exactly the inverse way as REST which blocks neuronal genes in many non-neuronal cell types. In summary, our data suggest that for optimal reprogramming results it may be important to use a combination of specific activators of the target cell program and specific repressors of the donor and other non-target cell programs.
Dr. Wernig is an Associate Professor of Pathology at the Institute for Stem Cell Biology and Regenerative Medicine at Stanford University. He graduated with an M.D. Ph.D. from the Technical University of Munich where he trained in developmental genetics in the lab of Rudi Balling. After completing his residency in Neuropathology and General Pathology at the University of Bonn, he then became a postdoctoral fellow in the lab of Dr. Rudolf Jaenisch at the Whitehead Institute for Biomedical Research/ MIT in Cambridge, MA. In 2008, Dr. Wernig joined the faculty of the Institute for Stem Cell Biology and Regenerative Medicine at Stanford University where he has been ever since. He received an NIH Pathway to Independence Award and has since received many other awards, including the Cozzarelli Prize for outstanding scientific excellence from the National Academy of Sciences U.S.A. the Outstanding Investigator Award from the International Society for Stem Cell Research, the New York Stem Cell Foundation Robertson Stem Cell Prize, and more recently has been named a HHMI Faculty Scholar.
Dr. Wernig’s lab is interested in pluripotent stem cell biology and the molecular determinants of neural cell fate decisions. His laboratory was the first to generate functional neuronal cells reprogrammed directly from skin fibroblasts, which he termed induced neuronal (iN) cells. The lab is now working on identifying the molecular mechanisms underlying induced lineage fate changes, the phenotypic consequences of disease-causing mutations in human neurons and other neural lineages as well as the development of novel therapeutic gene targeting and cell transplantation-based strategies for a variety of monogenetic diseases.
Maximina Yun | Center for Regenerative Therapies TU Dresden, Germany
Salamanders are vertebrates with extensive regenerative abilities, being capable of regenerating complex structures such as limbs in the adult stage. Limb loss triggers the generation of a mass of cells that dedifferentiate and re-enter the cell cycle to proliferate, named a blastema, and the set up of a morphogenetic programme which leads to the restoration of the missing structures. Unlike mammals, salamanders are able to stage numerous rounds of regeneration throughout their lives without losing regenerative potential. Furthermore, cell lines derived from the blastema exhibit an indefinite lifespan in culture, without undergoing replicative senescence. This suggests the possibility that mechanisms for the regulation of senescence may operate in salamanders. Indeed, our research has shown that salamanders have a highly efficient immune-dependent mechanism to clear senescent cells. Paradoxically though, our work also suggests that senescent cells have important functions during regeneration of complex structures. In this talk, I will discuss our recent evidence supporting a requirement for transient senescent cells during limb regeneration, as well as insights into how replicative senescence is controlled in these remarkable organisms.
I carried out my PhD studies at Cambridge University, at the MRC-Laboratory of Molecular Biology, in the area of DNA repair. I investigated the interplay between different DNA repair pathways and their regulation throughout the cell cycle. During my PhD studies I became interested in regenerative biology and joined one of the leading labs in the field, Jeremy Brockes’ lab at University College London, to work on the mechanisms underlying regeneration of complex structures using salamander as a model organism. After 6 years as a research fellow I became an independent researcher at UCL. In September 2017 I was recruited as a group leader at the Center for Regenerative Therapies in Dresden, Germany. My current research exploits the salamander system in order to understand the mechanisms underlying cell plasticity, the role of the immune response in regenerative contexts and the interplay between cellular senescence and regeneration.
Selected Short Talks
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