Forum Scientium Study Visit Boston 2012

Anders Elfwing Erik Martinsson

Camilla Halvarsson

April, 2012

Preliminary Visit Schedule

Monday morning

1. Center for Neurologic

diseases 2. Karp Lab

Monday afternoon Cancer vaccine center + Dana Farber cancer institute (whole group)

Tuesday morning 1. Center for Nanoscale

systems (9-11) + prof Charles Lieber (12-14)

2. Millipore

Tuesday afternoon 1. Samuel Adams Brewery

2. Dept. of Surgery 3. Merrimack

Wednesday morning 1. Mundel Lab

2. Langer Lab 3. David. Koch Inst.

Wednesday afternoon 1. Hemostasis and

thrombosis

2. Kaplan Lab

Monday morning

1. Center for Neurologic Diseases (Harvard)

Host: Dr. Daniel Kanmert

Dr. Daniel Kanmert

The Center for Neurologic Diseases is a group of multidisciplinary biomedical research laboratories which has its central objective in the application of a wide range of current biological methods to the elucidation of the pathogenesis and treatment of certain chronic, unsolved neurological diseases: multiple sclerosis, Alzheimer's disease and Parkinson’s Disease. In addition to clinically related research many of the laboratories have an additional focus directed at understanding basic human and animal immunology.

Link: http://www.brighamandwomens.org/research/CND/default.aspx

2. Karp Lab

Host: Dr. Jeffrey Karp

The laboratory aims to create advanced biomaterials and devices for therapeutics through a highly multidisciplinary approach. Through working at the interface of material science, biology engineering, and medicine, our highly interactive and collaborative group engages outstanding scientists and clinicians at MIT, Harvard, Brigham and Women’s Hospital and surrounding hospitals and institutions. A major focus of our group is the study and development of polymers and stem cells for addressing the biggest limitations in engineering replacement tissues and organs. We have a moral obligation not only to solve problems that can benefit patients of the future but also to develop strategies that can rapidly be translated to the clinic to help patients today. Therefore, we attempt to examine our strategies within in vivo models as soon as possible. This facilitates the pertinent gain of knowledge for potential translational barriers that we may encounter so that we can begin problem solving the key hurdles as early as possible.

Link: www.karplab.net

Selected publications: Cellular and extracellular programming of cell fate through engineered intracrine-, paracrine-, and endocrine-like mechanisms. Sarkar D, Ankrum JA, Teo GS, Carman CV, Karp JM. Biomaterials. 2011 Jan 22. Engineered cell homing. Sarkar D, Spencer JA, Phillips JA, Zhao W, Schafer S, Spelke DP, Mortensen LJ, Ruiz JP, Vemula PK, Sridharan R, Kumar S, Karnik R, Lin CP, Karp JM. Blood. 2011 Dec 15;118(25):e184-91. Cell-surface sensors for real-time probing of cellular environments. 1. Zhao W, Schafer S, Choi J, Yamanaka YJ, Lombardi ML, Bose S, Carlson AL, Phillips JA, Teo Q, Droujinine IA, Cui C, Jain RK, Lammerding J, Love JC, Lin CP, Sarkar D, Karnik R, Karp JM. Nature Nanotechnology, 2011

Dr. Jeffrey Karp

Monday afternoon

Cancer vaccine center

Host: Ellis L. Reinherz

Located at the DFCI in Boston, the CVC is developing new vaccines for treating people with cancer. The CVC is committed to excellence in basic science, vaccine development, and translation into clinical applications. CVC fosters efficient and effective interdisciplinary collaborations bringing together research scientists and clinicians and providing them with access to leading edge technology and facilities including bioinformatics, mass spectrometry, structural biology, immune assessment, nanotechnologies, immunoproteomics and immunogenetics. CVC simultaneously supports scientific discovery, preclinical vaccine development, clinical investigation, and development of diagnostics and therapeutics. The research pipeline at CVC is being used for rational design and development of effective vaccines and immunotherapies. Agenda: 1. Overview of the CVC: Interface of basic and translational immunology (Ellis Reinherz, CVC Director - 15 min) 2. Bioinformatics: Information technologies and knowledge acquisition (Vladimir Brusic, Director of Bioinformatics, CVC - 15 min) 3. Mass spectrometry: Ion physics as a path to identification of tumor antigens (Bruce Reinhold, Director of Proteomics, CVC - 15 min) 4. Targeting HIV to elicit broadly neutralizing antibodies (Mikyung Kim – 15 min) 5. Avoiding the next global influenza pandemic via T cell-based vaccines (Derin Keskin - 15 min)

Prof. Ellis L. Reinherz

6. Student presentation (Christian Simon - 15 min) 7. Talk to scientists and tour of CVC facilities - 30 min (5 groups) Link: http://www.dfhcc.harvard.edu/membership/profile/member/866/0/ Selected publications: Molecular Detection of Targeted Major Histocompatibility Complex I-Bound Peptides Using a Probabilistic Measure and Nanospray MS(3) on a Hybrid Quadrupole-Linear Ion Trap. Reinhold B, Keskin DB, Reinherz EL. Anal Chem. 2010 Oct 8 A conserved E7-derived cytotoxic T lymphocyte epitope expressed on human papillomavirus 16-transformed HLA-A2+ epithelial cancers. Riemer AB, Keskin DB, Zhang G, Handley M, Anderson KS, Brusic V, Reinhold B, Reinherz EL. J Biol Chem. 2010 Sep 17;285(38):29608-22.

Dana Farber Cancer Institute (DFCI)

The Postdoc and Graduate Student Association (PGA) helps postdocs and graduate students at Dana Farber Cancer Institute to expand their research training by offering a variety of services to enhance their professional development. Three students from PGA will organize the study visit; Hilary Wade (in the group of prof. Myles Brown), Tobias Otto (in the group of prof. Peter Sicinski), Miia Suuriniemi (in the group of Matthew Freedman). Host: Hilary Wade/Myles Brown: Medical Oncology.

Estrogen plays a critical role in the development of the normal breast and in breast cancer. The biochemical mechanisms underlying these processes, however, remain largely unknown. The overall aim of our current research is to build on recent advances in the molecular understanding of estrogen receptor (ER) action to better define the role played by estrogen in the normal breast and in breast cancer. Over the past few years several important coregulatory molecules that play a central role in mediating the transcriptional activity of ER have been identified by several labs including our own. Our current hypothesis is that the differential expression of these molecules accounts in part for the tissue specific

activity of selective estrogen receptor modulators (SERMs) such as tamoxifen and raloxifene. In addition, the gene encoding one of these ER coactivators, AIB1, was cloned as a gene Amplified In Breast cancer raising the possibility that altered expression of an ER coactivator may play a central role in estrogen-stimulated breast cancer growth. Our work will provide a better understanding of the role played by alterations in estrogen signaling in breast cancer. Identification of those factors which are markers for these changes are likely to lead to the development of better diagnostic and predictive tools. More importantly, the identification of the factors which are the critical regulators of the alterations in estrogen signaling will become new therapeutic targets and may lead to the development of improved strategies for the prevention and treatment of breast cancer. Link: http://www.dfhcc.harvard.edu/membership/profile/member/675/0/ Selected publications: Wade HE, Kobayashi S, Eaton ML, Jansen MS, Lobenhofer EK, Lupien M, Geistlinger TR, Zhu W, Nevins JR, Brown M, Otteson DC, McDonnell DP.Multimodal regulation of E2F1 gene expression by progestins.Mol Cell Biol. 2010 Apr;30(8):1866-77. Madak-Erdogan Z, Lupien M, Stossi F, Brown M, Katzenellenbogen BS.Genomic Collaboration of Estrogen Receptor-{alpha} and ERK2 in Regulating Gene and Proliferation Programs.Mol Cell Biol. 2011 Jan;31(1):226-36.

Prof. Myles Brown

Host: Tobias Otto/Peter Sicinski, Cancer Biology

The proliferation of mammalian cells is tightly controlled by numerous external signals. After they are received by the cells, these growth-promoting or growth-inhibitory signals are transmitted to the so-called cell-cycle machinery operating in the nucleus. The cell-cycle machinery is present in every single cell, and it can be thought of as the molecular engine that drives cell proliferation. The key components of this machinery are proteins termed cyclins. Abnormal expression of cyclins is seen in a great number of human cancers. For example, more than 50% of human breast cancers contain highly elevated levels of a particular cyclin protein, termed cyclin D1.

Importantly, because agents that antagonize this cyclin have been shown to shut off the proliferation of breast cancer cells grown in vitro, overexpression of cyclin D1 seems to play a causative role in mammary tumorigenesis. To understand the role played by these various cyclin proteins in normal development and in cancer, we generated several genetically engineered 'knockout' mouse strains lacking different cyclin proteins. We found that each of these proteins is required for proliferation in a very narrow, highly specific sets of tissues. For example, we discovered that cyclin D1-deficient mice develop hormone-insensitive mammary glands. Hence, the normal, physiologic role for cyclin D1 is to drive hormone-induced mammary epithelial proliferation, while overexpression of the very same cyclin plays a causative role in human breast cancers. We are currently using these knockout strains, and cells derived from them, as tools to study the role of particular cyclin proteins in normal cell proliferation and in oncogenesis of breast cancers, in particular. Moreover, we are generating novel mutant mouse strains that will help explain the role of cell-cycle machinery at the organismal, cellular, and molecular levels. Link: http://www.dfhcc.harvard.edu/membership/profile/member/738/0/ Selected publications: Odajima J, Kalaszczynska I, Sicinski P.Cyclins A and E trigger DNA damage.Cell Cycle. 2010 Dec 17;9(7):1231-2. Cole AM, Myant K, Reed KR, Ridgway RA, Athineos D, Van den Brink GR, Muncan V, Clevers H, Clarke AR, Sicinski P, Sansom OJ.Cyclin D2-cyclin-dependent kinase 4/6 is required for efficient proliferation and tumorigenesis following Apc loss.Cancer Res. 2010

Prof. Peter Sicinski

Host: Miia Suuriniemi/Matthew Freedman: Medical Oncology.

Many of the common risk alleles discovered to date in genome wide association scans are located in non-protein coding regions. A primary focus of our laboratory is to understand the gene or genes that these variants are acting through. We are adopting a variety of approaches and techniques to develop an approach that will inform our understanding of the functional consequences of risk alleles that are outside of protein coding regions. Another focus of the laboratory is to gain a deeper understanding of the link between the germline and tumor genomes.

Link: http://www.dfhcc.harvard.edu/membership/profile/member/25/0/ Selected publications: Sun T, Mary LG, Oh WK, Freedman ML, Pomerantz M, Pienta KJ, Kantoff PW.Inherited Variants in the Chemokine CCL2 Gene and Prostate Cancer Aggressiveness in a Caucasian Cohort.Clin Cancer Res. 2011 Mar 15;17(6):1546-52. Pomerantz MM, Freedman ML.Genetics of prostate cancer risk.Mt. Sinai J. Med.;77(6):643-54. Agenda: 1. Transfer to the DFCI main campus (Tobias Otto) – 15min 2. Welcome and Refreshments at the Postdoc and Graduate Student Affairs Office, Smith building room 347 (Jennifer Molina, Tobias Otto) - 15min 3. Tour of the DFCI main campus (3 groups), including the new Yawkey Center for Cancer Care, the Confocal Microscopy Core Facility, the Flow Cytometry Core Facility, and the labs of either Myles Brown, Matthew Freedman, or Peter Sicinski (Hilary Wade, Miia Suuriniemi, Tobias Otto) – 1hour 4. Presentation and Discussion panel with four postdocs about their background, research topic, the transition to a postdoc and the application for postdoc positions (Hilary Wade, Miia Suuriniemi, Tobias Otto, Per Hydbring) – 1hour

Tuesday morning

1. Center for Nanoscale Systems

CNS was created by FAS in 1999 to assist and support the research community of Harvard University researchers and collaborators. The inclusion of CNS in the National Nanotechnology Infrastructure Network (NNIN) in 2004 has expanded that function to include any and all other members of the larger research community both local and national, academic and non-academic who conduct research in any aspect of the large and growing field of nanoscale science. CNS accomplishes this mission by purchasing, operating and maintaining large, centralized scientific facilities for use by users. CNS also provides training and assistance to users to ensure that the next generation of scientists has the knowledge to answer the questions being raised by the research of today. Development of new advanced facilities for the imaging and fabrication of nanoscale structures is also a high priority for CNS.

At the core of CNS is the 20+ member technical staff who have expertise in many diverse areas of nanoscience. We have skilled technical staff who are specialists in microscopy, nanofabrication, ion beams, X-ray systems, sample preparation, lithography and computational simulation. They are the life-blood of CNS as they maintain, operate and train users on our many scientific facilities.

Link: http://www.cns.fas.harvard.edu/about/index.php

Prof. Charles Lieber (Harvard)

Host: Prof. Charles Lieber

The Lieber group is focused broadly on science and technology at the nanoscale within a common intellectual vision – the bottom-up paradigm for nanoscale science and technology This paradigm rests on the design and synthesis nanoscale components – building blocks – that can be tailored down to the atomic scale and subsequently elaborated as single structures or assemblies to yield virtually any kind of functional structure or nanosystem, ranging from ultra-sensitive medical sensors to powerful nanocomputers, and also to explore new areas of science that exist, for example, at the interface between nanoelectronics and living cells and tissue. We are committed to realizing this intellectual vision through studies currently focused on four major areas: - New materials. - Nano-bio interface - Nanoelectronics and Computing - Nano-Enabled Energy Link: http://cmliris.harvard.edu/ Selected publications:

C.M. Lieber, “Semiconductor nanowires: A platform for nanoscience and nanotechnology,” MRS Bull. 36, 1052-1063 (2011).

W. Lu and C.M. Lieber, “Nanoelectronics from the bottom up,” Nature Mater. 6, 841-850 (2007).

Prof. Charles Lieber

2. Millipore

Headquartered in Billerica, Massachusetts, EMD Millipore has some 10,000 employees in 67 countries motivated by the potential of science for life through a portfolio of more than 40,000 products. Comprised of three business units—Bioscience, Lab Solutions, and Process Solutions— Merck Millipore is a top tier supplier to the life science industry, and serves as a strategic partner for scientists, engineers, and researchers.

Link: http://www.millipore.com/

Tuesday afternoon

1. Samuel Adams Brewery

The Boston Beer Company is America's leading brewer of handcrafted, full-flavored beers. Founder and Brewer, Jim Koch, brews Samuel Adams® beers using the time-honored, traditional four-vessel brewing process, and the world's finest all-natural ingredients. With over 30 distinctive, award-winning styles of beer, Samuel Adams offers discerning beer drinkers a variety of brews. The brewery has won more awards in international beer-tasting competitions in the last five years than any other brewery in the world. Samuel Adams is an independent brewery and brewing quality beer remains its single focus. While the Samuel Adams brand is the country’s largest-selling craft beer, it accounts for just under one percent of the U.S. beer market. The Company's flagship brand, Samuel Adams Boston Lager®, is brewed using the same recipe and traditional brewing processes that Jim Koch's great-great grandfather used in the mid 1800s. The result is a beer renowned by drinkers for its full flavor, balance, complexity, and consistent quality. The visit will include a guided tour in the brewery.

Link: http://www.samueladams.com

2. Dept. of Surgery

Host: Prof. Elof Eriksson, MD PhD, EJ Catersson, MD PhD and Johan Junker, PhD.

At the Laboratory for Wound Healing and Tissue Engineering we focus our research efforts on translational research with the ultimate aim of generating treatment options for patients. Specific research aims include: optimizing skin graft transplantation following large burns or trauma, composite tissue transplantation, generation of prevascularized bioactive scaffolds, cell therapy, in vivo gene delivery and increased understanding of the signaling involved in cell migration and proliferation. Suggested agenda: 1. Post-doctoral fellow at Harvard Medical School - How, When and Why? (Johan Junker) 2. Tissue Engineering in the clinic - From basic science to patient treatment. (EJ Caterson) 3. The face transplantation program - Clinical examples of composite tissue transplantation. (Elof Eriksson) Link: http://www.brighamandwomens.org/Departments_and_Services/surgery/services/PlasticSurg/documents/erikssonres.aspx Selected publications: Epidermal regeneration by micrograft transplantation with immediate 100-fold expansion. Hackl F, Bergmann J, Granter SR, Koyama T, Kiwanuka E, Zuhaili B, Pomahac B, Caterson EJ, Junker JP, Eriksson E. Plast Reconstr Surg. 2012 Mar;129(3):443e-452e. Comparison of healing parameters in porcine full-thickness wounds transplanted with skin micrografts, split-thickness skin grafts, and cultured keratinocytes. Kiwanuka E, Hackl F, Philip J, Caterson EJ, Junker JP, Eriksson E. J Am Coll Surg. 2011 Dec;213(6):728-35. Epub 2011 Oct 21.

Prof. Elof Eriksson

3. Merrimack Pharmaceuticals

Merrimack is a biopharmaceutical company discovering, developing and preparing to commercialize innovative medicines paired with companion diagnostics for the treatment of serious diseases, with an initial focus on cancer. Merrimack’s mission is to provide patients, physicians and the healthcare system with the medicines, tools and information on the diagnosis and treatment of illness through a more precise mechanistic understanding of disease. Merrimack seeks to accomplish this mission by applying its proprietary systems biology-based approach to biomedical research, which Merrimack calls Network Biology.

Link: www.merrimackpharma.com

Wednesday morning 1. Mundel Lab Host: Lisa Buvall/Prof. Peter Mundel

Our laboratory studies the regulation of the actin cytoskeleton by signaling networks in health and disease, with an emphasis on the regulation of Rho GTPase signaling by the synaptopodin family of actin-associated proteins in neurons, kidney podocytes and cardiac myocytes. In addition we study the regulation of cell-cell and cell matrix adhesion by CD80/B7-1. Link: http://receptor.mgh.harvard.edu/mundel/Mundel_lab/Welcome.html Selected publications:

Faul C, Donnelly M, Merscher-Gomez S, Chang YH, Franz S, Delfgaauw J, Chang JM, Choi HY, Campbell KN, Kim K, Reiser J, Mundel P. The actin cytoskeleton of kidney podocytes is a direct target of the anti-proteinuric effect of cyclosporine A. Nat Med. 2008. 14: 931-938

Faul C, Dhume A, Schecter A, Mundel P. Ca2+/Calmodulin-Dependent Kinase II, and Calcineurin Regulate the Intracellular Trafficking of Myopodin between the Z-Disc and the Nucleus of Cardiac Myocytes. Mol Cell Biol. 2007. 27: 8215-8227

Prof. Peter Mundel

2. Langer Lab (MIT) Host: Joseph A. Ryan/ Prof. David Langer

Our work is at the interface of biotechnology and materials science. A major focus is the study and development of polymers to deliver drugs, particularly genetically engineered proteins, DNA and RNAi, continuously at controlled rates for prolonged periods of time. Work is in progress in the following areas: - Investigating the mechanism of release from polymeric delivery systems with concomitant microstructural analysis and mathematical modeling. - Studying applications of these systems including the development of effective long-term delivery systems for insulin, anti-cancer drugs, growth factors, gene therapy agents and vaccines. - Developing controlled release systems that can be magnetically, ultrasonically, or enzymatically triggered to increase release rates.

Link: web.mit.edu/langerlab/

Selected publications: Langer, R., Perspectives and challenges in tissue engineering and regenerative medicine, Advanced Materials, 21: 3235-3236, 2009. Farokhzad, O. and Langer, R., Impact of Nanotechnology on drug delivery, ACS Nano, 3: 16-20, 2009. Khademhosseini, A., Vacanti, J., Borenstein, J. and Langer, R., Microscale technologies for tissue engineering and biology, Proceedings of the National Academy of Sciences, 103: 2480-2487, 2006.

Prof. Robert Langer

3. David Koch Institute (MIT)

Host: Dr. Tyler E Jacks

We are interested in the genetic events that contribute to the development of cancer. The focus of our research is a series of mouse strains engineered to carry mutations in genes known to be involved in human cancer. Using conventional and conditional loss-of-function and gain-of-function mutations in various tumor suppressor genes as well as the K-ras oncogene, we have constructed mouse models of non-small cell lung cancer, pancreatic cancer, astrocytoma, endometroid ovarian cancer, colon cancer, soft tissue sarcoma, retinoblastoma, and tumors of the peripheral nervous system. We also study the effects of these mutations on normal embryonic development and use cells derived from mutant animals to study the function of these genes in cell culture models. Link: http://ki.mit.edu/research Selected publications: Treating metastatic cancer with nanotechnology. Schroeder A, Heller DA, Winslow MM, Dahlman JE, Pratt GW, Langer R, Jacks T, Anderson DG. Nat Rev Cancer. 2011 Dec 23;12(1):39-50. doi: 10.1038/nrc3180. Review. Expression of tumour-specific antigens underlies cancer immunoediting. DuPage M, Mazumdar C, Schmidt LM, Cheung AF, Jacks T. Nature. 2012 Feb 8;482(7385):405-9. doi: 10.1038/nature10803.

Dr. Tyler E Jacks

Wednesday afternoon

1. Hemostasis and thrombosis (Harvard)

Host: Prof. Barbara C. Furie

Prof. Barbara C. Furie

The division of hemostasis and thrombosis is focused on understanding and treatment of bleeding and thrombotic disorders. Hematologists with a special interest in disorders of blood coagulation diagnose and manage patients with acquired and hereditary disorders (e.g., hemophilia) and thrombotic diseases that cause deep venous thrombosis and pulmonary embolism.

Link: http://www.bidmc.org/Research/Departments/Medicine/Divisions/HemostasisandThrombosis.aspx

Selected publications:

A conotoxin from Conus textile with unusual posttranslational modifications reduces presynaptic Ca2+ influx. Rigby AC, Lucas-Meunier E, Kalume DE, Czerwiec E, Hambe B, Dahlqvist I, Fossier P, Baux G, Roepstorff P, Baleja JD, Furie BC, Furie B, Stenflo J.Proc Natl Acad Sci U S A. 1999 May 11;96(10):5758-63.

Alpha-granule secretion from alpha-toxin permeabilized, MgATP-exposed platelets is induced independently by H+ and Ca2+. Flaumenhaft R, Furie B, Furie BC. J Cell Physiol. 1999 Apr;179(1):1-10.

2. Kaplan Lab (Tufts)

Host: Prof. David Kaplan

Research is focused at the interface between biology and materials science and engineering. Our research is aimed at understanding biological synthesis and processing of polymers and polymer interfaces. Issues of structure-function related to self-assembly and macromolecular assembly are key to this understudy. Activities are focused on biomaterials and functional tissue engineering. We approach this problem from three levels:

• Genetic Approach: Exploration of the molecular genetics of biosynthesis pathway for biopolymers.

• Whole Cell Approach: Manipulation of the Cell Environment to regulate the nature of the biopolymer synthesized.

• Enzymatic Approach: Polymer synthesis using enzymes in vitro in novel environments.

Link: http://engineering.tufts.edu/chbe/people/kaplan/index.asp

Selected publications:

Wang, X.; Zhang, X.; Castellot, J.; Herman, I.; Iafrati, M.; Kaplan, DL. (2008). Controlled release from multilayer silk biomaterial coatings to modulate vascular cell responses. Biomaterials 29(7):894-903

Mapping domain structures in silks from insects and spiders. E. Bini, D. Knight, D. L. Kaplan. J. Molecular Biology. 335:27-40 (2004).

Prof. David Kaplan