Willem M. Kuhtreiber, PhD
Email willem@kuhtreiber.net
Website http://www.kuhtreiber.net
EDUCATION
Ph.D. in Developmental Biology, Summa Cum Laude, University of Utrecht (The Netherlands), 1987
M.Sc. Biology, University of Nijmegen (The Netherlands), 1983
EXECUTIVE PROFILE
* Twenty-three years of research experience, including thirteen years in the biotech industry
* Detailed knowledge in the fields of diabetes, transplant immunology, cell transplantation and autoimmunity
* Proven capabilities in establishing new research directions, model systems and pilot studies
* Successful in attracting funding from National Agencies
* Holder of several cell encapsulation patents
* Experienced in managing the activities of R&D groups
RESEARCH EXPERIENCE
Aug 2010 - Present
Immunobiology Laboratory,
Massachusetts General Hospital/Harvard Medical School
Charlestown, MA
* Developing bioassays and biomarkers in autoimmune diseases such as Type 1 diabetes and Sjögren’s disease using advanced flow cytometry and high throughput automated Western Blotting and Isoelectric Focusing methods.
2008 - 2010
Prodo Laboratories, Inc. Irvine, CA
Chief Scientific Officer
* Define and lead the company’s scientific operations in areas of islet isolation, culture, physiology, transplantation, proliferation, and product development for both Type I and Type 2 diabetes.
* Hire, train and manage research staff
* Lead the company’s research and product development efforts
* Responsible for academic and corporate research collaborations and development of grant support.
* Completed projects include:
- Improved islet isolation and culture methods, achieving among the highest yield and quality in the industry.
- Developed new cGMP human islet media for recovery after isolation, long term culture, and shipping, that have been shown to be superior to current media.
- Designed and implemented company’s in vitro and in vivo islet testing, QC procedures, SOP documentation, as well as IT infrastructure.
2006 - 2008
City of Hope National Medical Center
Beckman Research Institute, Duarte, CA
Research Scientist IV
* Human islet isolation and isolation related research and development activities with a team of research associates. These activities support several clinical trials in human islet transplantation.
* Fundamental research with an emphasis on non-invasive imaging and assessment of transplanted islets and re-vascularization; secretion of cytokines by islets under stress and injury; and prevention and reversal of autoimmune diabetes.
April 2005 - Sept 2006
Novocell, Inc. Irvine, CA
Director of Cell Biology
* Oversaw research staff of 12 scientists and research associates, including 3 PhDs. Research activities included Phase I/II clinical trial with encapsulated human primary islets, islet isolation, culture and physiology, islet proliferation, derived islets from adult and embryonic human stem cells, functional analysis of stem cell derived islets, islet cryopreservation and histology.
* Responsible for world’s first FDA approved Certificate of Analysis for primary human islets.
* Performed a Phase I/II clinical trial with implantable encapsulated human islets and developing procedures for culture scale up and functional testing of human stem cell derived islets.
* Revised large scale human islet isolation methods resulting in the doubling of the islet isolation yield. This enabled the performance of Phase I/II clinical trial using PEG encapsulated primary human islets as a new treatment for hypoglycemic unaware Type I diabetes patients.
* Developed methods that extended the culture time of free and encapsulated human islets from a few days to over one month, while maintaining excellent islet health suitable for clinical islet transplantation.
* Developed procedures that enabled the processing of human islets in a Class 10,000/100 clean room environment conforming to cGMP and cGTP requirements for the Phase I/II clinical trial.
* Established QC procedures for functional release criteria as well as FDA reporting requirements for a clinical trial with encapsulated human islets.
* Oversaw preparation of SOPs as required by cGMP guidelines.
2001 - 2005
Immunobiology Laboratory,
Massachusetts General Hospital/Harvard Medical School
Charlestown, MA
* Established lead compounds for the in vivo removal of pathogenic cells in the NOD mouse, a model for autoimmune (Type I) diabetes. The targeted destruction of these cells was shown to prevent disease in cell transfer experiments. Such procedures may ultimately lead to a cure for human Type I diabetes.
* Developed assays for the detection of pathogenic autoimmune cells involved in Type I diabetes. Investigating defects in the molecular pathways involving cytokine receptors, TOLL-like receptors and NF-kB that lead to accelerated apoptosis in autoimmune cells by flow cytometry, immunocytochemistry, histomorphometry and adoptive cell transfer.
* Screening of chemical libraries to identify lead compounds for the treatment of autoimmune disease.
* Investigated the mechanisms involved in the reversal of Type I diabetes and the creation of peripheral tolerance in autoimmune NOD mice. Induction of Tumor Necrosis Factor alpha (TNF-a) expression causes selective death of TNF-a sensitive T cells with proteasome defects. This results in the interruption of pancreatic islet directed autoimmunity. The reversal is then made permanent by re-education with MHC class I matched splenocytes, as well as transplantation of islets from non-autoimmune donors.
* Analyzed the involvement of pathogenic cells with heightened apoptosis sensitivity in autoimmune diseases other than Type I diabetes. This work Initially focused on NZB/NZM lupus mice.
* Investigated the role of Platelet Derived Growth Factor (PDGF) in restenosis and neo-intima formation after carotid balloon angioplasty in diabetic Zucker rats. Properties of arterial smooth muscle cells from fat and lean Zucker rats are compared by means of PDGF-induced migration and proliferation studies. Studying the expression of PDGF receptor tyrosine kinase in these cells by RT-PCR. Evaluating PDGF receptor inhibitors for effects on inhibition of neo-intima formation in diabetic rats.
* Responsible for writing of grant applications, as well as human and animal protocols
2002 - 2005
Vanderbilt University
Microgravity Science and Applications Center
Nashville, TN
Consultant
* Isolated canine pancreatic islets for allograft and xenograft transplantation into diabetic primates and dogs.
* Consulted on islet physiology and handling.
1997 - 2001
BioHybrid Technologies Inc, Shrewsbury, MA
Director of Islet Physiology
1992 - 1997
BioHybrid Technologies Inc., Shrewsbury, MA
Senior Scientist
* Managed technical staff involved in research, pancreatic islet isolation, culture, QC and RIA. Oversaw radiation safety and GLP/GMP issues.
* Established innovative cell encapsulation and immunoisolation technologies for the treatment of diabetes and other diseases by means of cell therapy with encapsulated allografts and xenografts. Developed biodegradable matrices and permselective barriers for cell encapsulation, allotransplantation, xenotransplantation and tissue engineering applications. Studied mechanisms of graft rejection and transplant immunology.
* Developed methods for isolation, primary culture and QC of pancreatic islets from porcine, bovine, canine and human pancreas. Developed methods for the in vitro proliferation of pancreatic beta cells from isolated islets and islet stem cells. Developed a new method for the simultaneous encapsulation and cryopreservation of large numbers of pancreatic islets.
* Developed anti-fibrotic and anti-inflammatory strategies, including ultra-purification of encapsulation materials, systemic and local antifibrotic treatments, inclusion of antifibrotic substances in the microcapsule design, and scavenging of antigens. These strategies are based on my investigations of the mechanisms of host foreign body reactions, macrophage activation and cytokines involved in the fibrosis of peritoneal implants and graft rejection.
* Oversaw studies of the involvement of Gibbs-Donnan equilibria, solute imbalance, osmotic pressure differentials and Flory-Huggins polymer-solution interactions in the steady state of micro reactors.
* Four patents and several disclosures were awarded for this research.
* Determined research directions and designed pilot studies.
* Responsible for writing of grant applications.
1991 - 1992
Howard Hughes Medical Institute, Boston, MA
Assistant Researcher, Lab. for Molecular Endocrinology, MGH, Boston
Assistant in Biochemistry, Massachusetts General Hospital (MGH)
Instructor, Harvard Medical School
* Discovered priming action of Glucagon-Like Peptide 1 (GLP1) on glucose sensitivity of pancreatic beta cells.
* Determined GLP1 action on electrical activity, second messenger signaling, and stimulated insulin secretion in pancreatic beta cells using patch clamp electrophysiological recording techniques.
* Collaborated in expression cloning and molecular characterization of the GLP1 receptor from a cDNA library.
1987 - 1991
Marine Biological Laboratory, Woods Hole, MA
National Vibrating Probe Facility (NVPF, NIH)
Assistant Scientist
* Developed an ion selective vibrating probe system and used it in determining the significance of ion fluxes and ion gradients in fertilization, development and differentiation. This method continues to be used by residents and visiting scientists at the NVPF.
* Discovered the mechanisms of post-fertilization calcium and proton loss in eggs of sea urchins and ascidians. Investigated the roles of calcium and proton signaling in embryogenesis of equal cleaving molluscs.
* Determined the role of calcium in differentiation of Dictyostelium; locomotion of Amoeba; establishment of electrical polarity in the ovarian follicles of insects; polarization of the fucoid sea weed Pelvetia; growth of Funaria.
1983 - 1987
Summa Cum Laude Ph.D.
University of Utrecht (The Netherlands).
Department of Experimental Zoology
* Awarded four year Fellowship from the Dutch Organization for Fundamental Scientific Research (ZWO).
* Determined the role of cellular interactions involved in mesoderm induction and differentiation during early embryonic development of molluscs.
* Discovered extracellular matrix (ECM) between cells involved in mesoderm induction.Developed monoclonal antibodies against ECM. Characterized ECM using cytochemical and immuno-cytochemical techniques at electron microscopic and light microscopic levels.
* Developed innovative micro-injection and laser-based fluorescence techniques to analyze the role of ECM in mesoderm induction. Discovered exo/endocytosis signalling pathway involved in mesoderm determination using cellular tracer techniques.
SPECIFIC SKILLS
Human Adult and Embryonic Stem Cells, Flow Cytometry, Tissue Engineering, Adoptive Cell Transfer, Cellular Therapy, Cell Encapsulation and Immuno Isolation, Polymer Chemistry, Biocompatibility Assays, ELISA, RIA, Gibbs-Donnan Equilibria, Histology, Cytochemistry, Immuno-Cytochemistry, Pancreatic Islet Isolation and Culture, Small Animal Surgery, Diabetic Animal Models, Isolation and Culture of Primary Mammalian Cells, Expression Cloning, Molecular Biology, LAL Assays, Apoptosis, Migration and Proliferation Assays, Monoclonal Antibody Production, Electron Microscopy (TEM, SEM, Immuno-), Patch Clamping (Perforated, Whole Cell, Single Channel), Iontophoresis, Calcium Imaging, Voltage and Ion-Specific Vibrating Probe, Microinjection and Micromanipulation Techniques, Analog and Digital I/O Programming, Windows, Linux, Web Design, C, Forth, Basic, PERL, PHP
MEMBERSHIPS
American Diabetes Association (ADA) Bioencapsulation Research Group (BRG) Boston-Ithica Islet Club American Association for the Advancement of Science (AAAS) Strathmore’s Who’s Who
CONTINUED EDUCATION
Operations Management (MBA level), Harvard University Extension School.
LANGUAGES
English, Dutch, German, French
REFERENCES
References are available upon request.
PUBLICATIONS
Journal Articles and Recent Abstracts
Serras F, Kuhtreiber WM, Krul MR and van den Biggelaar JAM (1985) Cell communication compartments in molluscan embryos. Cell Biol Int Rep 9: 731-736
Kuhtreiber WM, van der Bent, J, Dorresteijn AWC, de Graaf A, van den Biggelaar JAM and van Dongen CAM (1986) The presence of an extracellular matrix between cells involved in the determination of the mesoderm bands in embryos of Patella vulgata (Mollusca, Gastropoda). Wilhelm Roux’s Arch Dev Biol 195: 265-275
van den Biggelaar JAM, Kuhtreiber WM, Serras F, Dorresteijn AWC, Beekhuizen H and Schaap D (1986) Analysis of cell communication mechanisms involved in the induction of the stem cell of the mesodermal bands in embryos of Patella vulgata (Mollusca), Acta Histochem suppl 32: 29-33
Kuhtreiber WM (1987) Character and morphogenetic significance of cell communication in the determination of the mesodermal cell line in molluscs. Ph.D. Thesis, University of Utrecht, The Netherlands.
Kuhtreiber WM and Serras F (1987) Direct microinjection of substances in penetration-sensitive embryos. Differentiation 34: 156-159
Kuhtreiber WM, Serras F and van den Biggelaar JAM (1987) Spreading of microinjected horseradish peroxidase to non-descendant cells in embryos of Patella (Mollusca, Gastropoda). Development 100: 713-722
Kuhtreiber WM, van Til EH and van Dongen CAM (1988) Monensin interferes with the determination of the mesodermal cell line in embryos of Patella vulgata. Wilhelm Roux’s Arch Dev Biol 197: 10-18
Kuhtreiber WM and van Dongen CAM (1989) Microinjection of lectins, hyaluronidase and hyaluronate fragments interferes with cleavage delay and mesoderm induction in embryos of Patella vulgata. Dev. Biol. 132: 436-441
Kuhtreiber WM and Jaffe LF (1990) Detection of extracellular calcium gradients with a calcium specific vibrating electrode. J. Cell Biology 110: 1565-1573.
Gillot I, Chrystal J, Jaffe LF and Kuhtreiber W.M. (1990) Where does the calcium lost by fertilizing Arbacia eggs go to? Biol. Bull. 179: 224
Kochian LV, Shaff JE, Kuhtreiber WM, Jaffe LF and Lucas WJ (1992) Use of an extracellular, ion-selective, vibrating microelectrode system for the quantification of H+, K+, and Ca2+ fluxes in maize roots and maize suspension cells. Planta 188: 601-610
Holz GH, Kuhtreiber WM and Habener JF (1992) Induction of glucose competence in pancreatic beta cells by glucagon-like peptide-1(7-37). Trans Assoc Am Physicians 105: 260 - 267
Kuhtreiber WM, Gillot I, Sardet C and Jaffe LF (1993) Net calcium and acid release at fertilization in eggs of sea urchins and ascidians. Cell Calcium 14: 73-86
Holz GH, Kuhtreiber WM and Habener J (1993) Pancreatic beta-cells are rendered glucose-competent by the insulinotropic hormone glucagon-like peptide-1(7-37). Nature 361: 362 - 365
Kuhtreiber WM, Lanza RP, Beyer AM, Kirkland KS, Solomon BA, Muller TE and Chick WL (1993) Relationship between insulin secretion and oxygen tension in hybrid diffusion chambers. ASAIO J 39: M247-251
Kuhtreiber WM, Lanza RP and Chick WL (1994) Secretory function of biohybrid pancreas devices containing isolated porcine islets. ASAIO Journal, 40: M789-792
Kuhtreiber WM, Lanza RP and Chick WL (1994) Bovine islet isolation. In: “Pancreatic Islet Transplantation Series. Volume I: Procurement of Pancreatic Islets”, edited by R.P. Lanza and W.L. Chick (R.G.Landes Company/Medical Intelligence Unit: Austin,TX, 1994 [distributed by CRC Press]). pp.71-80
Lanza RP, Beyer A, Kuhtreiber WM and Chick, WL (1994) Humoral responses to encapsulated islets. Transplantation Proceedings 26: 3346 - 334
Lanza RP, Beyer A, Kuhtreiber WM and Chick WL (1994) Host sensitization by antigens from the biohybrid artificial pancreas. ASAIO J 23: 13Lanza RP, Beyer A,
Kuhtreiber WM and Chick, W.L (1994) Xenogeneic humoral responses to encapsulated islets. Hormone and Metabolic Research, 26: 70
Lanza, RP, Kuhtreiber WM, and Chick WL (1994) Islet transplantation using immunoisolation. Artifical Cells, Blood Substitutes, and Immobilization Biotechnology 22: A26
Lanza, RP, Kuhtreiber WM and Chick WL (1994) Biohybrid devices: Future considerations. Introduction and historical background. In: “Pancreatic Islet Transplantation Series. Volume III: Immunoisolation of Pancreatic Islets”, edited by R.P. Lanza and W.L. Chick (R.G. Landes Company/Medical Intelligence Unit: Austin, TX, 1994 [distributed by CRC Press]). pp.175-180.
Lanza RP, Kuhtreiber WM, Ecker DM, Staruk JE and Chick WL (1995). Xenotransplantation of porcine and bovine islets without immunosuppression using uncoated alginate microspheres. Transplantation 59:1377-1384
Lanza RP, Kuhtreiber WM, Ecker DM, Marsh JP, Staruk JE and Chick WL (1995) A simple method for transplanting discordant islets into rats using alginate gel spheres. Transplantation, 59: 1485 - 1487
Lanza RP, Kuhtreiber WM, and Chick WL (1995) Encapsulation technologies. Tissue Engineering 1: 181-196
Lanza RP, Kuhtreiber WM, Ecker DM, Marsh JP, Staruk, JE and Chick WL (1995) Successful bovine islet xenografts in rodents and dogs using injectable microreactors. Transplantation Proceedings 27: 3211
Lanza RP, Ecker DM, Kuhtreiber WM, Staruk JE, Marsh JP and Chick WL (1995) A simple and inexpensive method for transplanting discordant xenogeneic islets into rats using alginate gel spheres. Transplantation Proceedings 27: 3322
Lanza RP, Kuhtreiber WM, Ecker DM, Staruk JE and Chick WL (1995) Transplantation of porcine and bovine islets into mice without immunosuppression using uncoated alginate microspheres. Transplantation Proceedings 27: 3321
Lanza, RP, Kuhtreiber WM, Ecker DM, Marsh JP, Staruk JE, Carr S and Chick WL (1996) Xenotransplantation of bovine islets into rodents and dogs without immunosuppression using injectable microreactors. Transplantation Proceedings 28: 830
Lanza, RP, Kuhtreiber WM, Ecker DM, Marsh JP and Chick WL (1996) Preclinical trials using porcine and bovine islets immobilized inside biodegradable microreactors. Diabetes 45: 257A
Lanza RP, Kuhtreiber WM, Ecker DM, Marsh JP, Ringeling J, Staruk JE, and Chick WL (1996) Successful transplantation of encapsulated islets into diabetic rats, rabbits, and NOD mice without immunosuppression. Cell Transplantation 5(5S-2):52
Lanza, RP, Ecker DM, Marsh JP, Kuhtreiber WM, Staruk JE and Chick WL (1996) A simple method of xenotransplanting cells and tissues using uncoated alginate spheres. Transplantation Proceedings 28: 830
Lanza RP, Ecker DM, Kuhtreiber WM, Marsh JP, Ringeling J, and Chick WL (1999) Transplantation of islets using microencapsulation: studies in diabetic rodents and dogs. J Molecular Medicine 77: 206 - 210
Lanza RP and Kuhtreiber WM (1999) Xenotransplantation and Cell Therapy: Progress and Controversy. Molecular Medicine Today 5: 105-106
Lanza RP, Jackson R, Sullivan A, RingelingJ, McGrath C, Staruk J, Kuhtreiber WM and Chick WL (1999) Xenotransplantation of cells and tissues using biodegradable microcapsules. Transplantation 67: 1105-1111
Kuhtreiber WM, Lanza RP and Chick WL (1999) Artificial Pancreas. In: “Encapsulated Cell Technology and Therapeutics” (Kuhtreiber, W.M., Lanza, R.P., and Chick, W.L., Editors) Birkhauser Boston, pp. 217-228
Zimmermann U, Hasse C, Rothmund M and Kuhtreiber WM (1999) Biocompatible encapsulation Materials: Fundamentals and Application. In: “Encapsulated Cell Technology and Therapeutics” (Kuhtreiber WM, Lanza RP and Chick WL, Editors) Birkhauser Boston, pp. 40 - 52
Kuhtreiber WM (1999) Crossing the Species Barrier. Investigational Drugs Weekly Highlights 51: 32-35
Kuhtreiber WM, Hayahsi T, Dale EA, Faustman DL (2003) Central role of defective apoptosis in autoimmunity. J Molec Endocrinol 31: 373-399
Kodama S, Kuhtreiber WM, Fujimura S, Dale EA and Faustman DL (2003) Islet regeneration during the reversal of autoimmune diabetes in NOD mice. Science 302: 1223-1227
Finn AV, Clermont A, Kolodgie F, Giese N, Kuhtreiber WM, Dale EA, Virmani R, Gold H (2003) A Novel Animal Model of Arterial Stenting in Type II Diabetes Mellitus: Effect of PDGF Inhibition on Neointimal Formation. American Heart Association’s Scientific Sessions. November 9-12, 2003; Orlando, FL
Kuhtreiber WM, Kodama S, Burger DE, Dale EA and Faustman DL (2005). Methods to characterize lymphoid apoptosis in a murine model of autoreactivity. J Immunol Methods 30: 137-150
Ho LT, Zebadua E, Kao P, Urrutia T, Orr C, Ferreri K, Kandeel F and Kuhtreiber WM (2008) Secretion of injury factors by human islets after isolation and hypoxia. 8th Annual Rachmiel Levine Symposium, Newport Beach, CA
Wang T, Adcock J, Kuhtreiber W, Qiang D, Salleng KJ, Trenary I, Williams P (2008). Successful allotransplantation of encapsulated islets in pancreatectomized canines for diabetic management without the use use of immunosuppression. Transplantation 85: 331-337.
Ban L, Zhang J, Wang L, Kuhtreiber W, Burger D, Faustman DL (2008) Selective death of autoreactive T cells in human diabetes by TNF or TNF receptor 2 agonism. Proc Natl Acad Sci USA 105: 13644-13649
Kuhtreiber WM, Ho LT, Kamireddy A, Yacoub JAW, Scharp DW (2009) Use of Roche cGMP Liberase MTF C/T in islet isolation from human pancreas with extended cold ischemia time (CIT). 9th Annual Rachmiel Levine Diabetes and Obesity Symposium, Anaheim, CA
Kuhtreiber WM, Ho LT, Kamireddy A, Yacoub JAW, Scharp DW (2009) Islet isolation from human pancreas with extended cold ischemia time (CIT). Abstract and Oral Presentation, IPITA-IXA 2009, Venice, Italy
Kuhtreiber WM, Ho LT, Kamireddy A, Yacoub JAW, Scharp DW (2009) Islet cell isolation from human pancreas with extended cold ischemia time (CIT). Roche Cell Isolation Application Note 1: 1-4
Kuhtreiber WM, Ho LT, Kamireddy A, Yacoub JAW, Scharp DW (2010) Islet isolation from human pancreas with extended cold ischemia time. Transplant Proc 42:2027-2031
Mirbolooki M, Bozorgmanesh H, Foster CE, Kuhtreiber WM, Lakey JRT (2011) Tissue and Cell Isolation. In: Comprehensive Biotechnology, 2nd edition. Moo-Young M, Butler M. (Eds.), Volume 1, Chapter 44, pp 591-598. Elsevier
Burger DE, Wang L, Ban L, Okubo Y, Kuhtreiber WM, Leichliter AK and Faustman DL (2011) Novel Automated Blood Separations Validate Whole Cell Biomarkers. PLoS ONE 6(7): e22430. doi:10.1371/journal.pone.0022430
Books
Kuhtreiber WM, Lanza RP and Chick WL (Editors): Encapsulated Cell Technology and Therapeutics. Birkhauser Boston, 1999
Kuhtreiber WM (1987) Character and morphogenetic significance of cell communication in the determination of the mesodermal cell line in molluscs. Ph.D. Thesis, University of Utrecht, The Netherlands
Patents
Lanza RP, Kuhtreiber WM and Chick WL (2000) Microcapsules and Composite Microreactors for Immunoisolation of cells. US Patent 6,126,936
Lanza RP, Kuhtreiber WM and Chick WL (2000) Immunoisolation. Australian Patent 721726
Lanza RP, Kuhtreiber WM and Chick WL (1999) methods of use of uncoated gel particles. US Patent 5,912,005
Lanza RP, Kuhtreiber WM and Chick WL (1997) Methods of use of uncoated gel particles. US Patent 5,651,980
Lanza RP, Kuhtreiber WM and Chick WL (1996) Immunoisolation. International Patent PCT - WO96/28029