PHYL 548B Advanced Topics in Human Physiology: Stem Cells and Regenerative Medicine – What does the Future Hold?

Stem Cells and Regenerative Medicine: What does the Future Hold?
Regenerative Medicine has the potential to revolutionize medical practice, with cell therapy emerging as a powerful treatment option for a variety of debilitating diseases.  This course will introduce students to the promises but also the challenges that lie ahead in realizing this potential.

Canadians Jim Till and Ernest McCulloch had a pivotal role in the history of stem cell science, being the first researchers to prove the existence of stem cells in the 1960s.  Stem cells have the remarkable potential to develop into many different cell types in the body during early life and growth.  In addition, in many tissues they serve as an internal repair system, dividing essentially without limit to replenish other cells as needed.  When a stem cell divides, each new cell has the potential to either remain a stem cell or become another type of cell with a more specialized function, such as a muscle cell, a red blood cell, a brain cell, or an insulin producing cell.

Today, donated organs and tissues are often used to replace ailing or destroyed tissue, but the need for transplantable tissues and organs far outweighs the available supply.  Stem cells, directed to differentiate into specific cell types, offer the possibility of a renewable source of replacement cells and tissues to treat diseases including macular degeneration, spinal cord injury, stroke, burns, heart disease, diabetes, and arthritis.

In 1998, scientists developed methods to isolate embryonic stem cells from fertilized human embryos.  The embryos used in these studies were created for reproductive purposes through in vitro fertilization procedures.  When they were no longer needed for that purpose, they were donated for research with the informed consent of the donors.  The embryonic stem cells derived from these embryos have the capacity for virtually unlimited cell division, but also the differentiation into all of the >200 cell types that make up the human body, thereby possessing tremendous therapeutic potential.  The Food and Drug Administration (FDA) approved the first clinical trial in the United States involving human embryonic stem cells in 2009 for the treatment of spinal cord injury.  Other trials have since been approved for eye disease and diabetes.  However, much work remains to be done in the laboratory and the clinic to understand how to effectively use these cells for cell-based therapies to treat disease, which is also referred to as regenerative medicine.

Despite their promise, there are ongoing ethical debates regarding the derivation and use of embryonic stem cells.  A major advance came in 2006, when Japanese scientists developed tools to make stem cells from adult cells, such as can be readily obtained from skin or blood.  These “induced pluripotent stem cells” are adult cells that have been genetically reprogrammed to an embryonic stem cell-like state by being forced to express genes and factors important for maintaining the defining properties of embryonic stem cells.  Aside from eliminating the ethical concerns associated with using cells derived from human embryos, these cells have the advantage of being perfectly matched to patients and thus not stimulating an immune response when transplanted.  In 2012, Professor Shinya Yamanaka received the Nobel Prize in Medicine for this ground-breaking research.

Aside from use as potential therapies, human stem cells are being used widely to model diseases and thereby reduce the use of animals for experimentation.  Techniques are being developed to differentiate stem cells into miniature human organs.  An organ-on-a-chip is a multi-channel 3-D microfluidic cell culture chip that simulates the activities, mechanics and physiological response of entire organs.  Researchers are working towards building a multi-channel 3D microfluidic cell culture system in which several 3D cellular aggregates of multiple cell types are cultured to mimic multiple organs in the body, a so-called human-on-a-chip.  Such systems may be very useful for drug testing, and to potentially measure direct effects of one organ’s reaction on another.  For instance, test substances could be screened to confirm that even though they may benefit one cell type, they do not compromise the functions of others.  Such studies may improve the likelihood that new drugs pass clinical trials.

A limitation of using induced pluripotent stem cells for therapy is the potential that they harbor one or more genetic mutations that contribute to disease onset.  This can now be addressed with powerful new genetic engineering approaches that are rapidly gaining widespread adoption, such as “CRISPR”.  CRISPR-Cas9 is a genome editing tool that is creating a buzz in the science world.  The system consists of two key molecules that combine to introduce a change into the DNA.  The enzyme Cas9 acts as a pair of ‘molecular scissors’ to cut the two strands of DNA at a specific location in the genome so that bits of DNA can then be added or removed.  A pre-designed piece of RNA called guide RNA (gRNA), with RNA bases that are complementary to those of the target DNA sequence in the genome, ‘guides’ Cas9 to the right part of the genome.  This ensures that the Cas9 enzyme cuts at the desired point.  The cell recognizes that the DNA is damaged and tries to repair it, at which point strategic changes to one or more genes can be made.  The combination of stem cells and genome editing is a very powerful and exciting approach for disease modeling and therapy.

With the successes also comes hype and false promises.  There have been many grim stories about the abuse of regenerative medicine and stem cell therapies in the headlines.  Hundreds of international stem cell clinics now hawk unproven, unregulated therapies to desperate people.  Such “stem cell tourism” often does more harm than good, detracting from the positive forward motion of regenerative medicine and the very real potential for individual patients and the national economy.

The next wave of regenerative medicine research is tackling enormous health care issues: AIDS, Alzheimer’s disease, diabetes, heart disease, blood cancers, and blindness, among others.  Despite the complexities, regenerative medicine, which encompasses stem cell research, tissue engineering, and gene therapy, has the potential to positively affect many clinical areas.  Academic institutions and responsible companies are working hard to unlock the potentially transformative impact of stem cells.  It is timely to introduce a graduate level course at UBC to engage both students and the public with reliable information on the current status of regenerative medicine and look to the future possibilities.  The course will also likely catalyze new initiatives and collaboration with UBC scientists.

The students will be exposed to the tools and techniques involved in developing cell based therapies for disease, the hurdles that need to be overcome and the processes that need to be followed to develop a product, including the path through pre-clinical and clinical trials, and the costs involved along the way.  Ten faculty and a medical reporter have agreed to participate in the course, including 5 external faculty who will share their perspectives on the successes and failures, and experience from bench to bedside.  Ethical issues will be discussed, along with examples of misplaced hype and false promises.  The role of academia and industry will be discussed, along with the role of funding from government and charitable organizations.  Students will finish the course with a greater understanding of the vast potential of stem cells and genetic engineering, the complexities of the field, and an appreciation of Canada’s contributions in this fast-moving field.

Course Name

PHYL 548B 002

Advanced Topics in Human Physiology: Stem Cells and Regenerative Medicine: What does the Future Hold?

Supported by Killam Connection Program

Course Co-ordinator

Timothy J. Kieffer, PhD

Professor, Department of Cellular & Physiological Sciences

604-822-2156

tim.kieffer@ubc.ca

kiefferlab.com

Schedule

Life Sciences Centre Room LSC1330

Wednesdays, 2018 Term 2 (Jan 3, 2018 to Apr 4, 2018)

13:00 to 16:00

This course will be comprised of 12 scheduled weekly classes, each 3 hours in length, plus 5 evening public lectures, for a total of ~41 hours

Location

All classes will be held in Life Sciences Centre Room LSC1330, 2350 Health Sciences Mall, UBC. All public lectures will occur in the Life Sciences Centre.

Credits

3

Course Requirements

There will be no pre-requisites for this course.

Students must bring a laptop computer to class for on-the-fly web searches.

Relevant reading material will be assigned and made available on the course website.  No textbooks will be used.

Learning Objectives

  • Understand the path and recognize the challenges of developing a cell-based therapy
  • Critique the hype and unsubstantiated claims in regenerative medicine
  • Report on public lectures via a blog post on course website
  • Appraise and interpret research publications of guest faculty
  • Achieve a professional (informed scholarly) identity while interfacing with the public
  • Complete and present a synopsis of a biotechnology company in the stem cell field

Mode of Assessment

  • Class and public lecture participation 20%
  • Class presentations / debates 20%
  • Online blog posting and editorial position statements, website content 30%
  • Final class assignment 20%
  • Assessment from peers 10%
Facilitator / Guest Topic

Timothy Kieffer, Ph.D.

Professor, University of BC

Course Coordinator

Wed Jan 3, 2018 (1-4PM)

Course overview; the path from basic science to product development for cell based therapies

Pamela Fayerman

Medical/Health Issues Reporter

The Vancouver Sun

Wed Jan 10, 2018 (1:30-4:30PM)

Responsible and effective communication of research to the public and interacting with the media

James Shapiro, M.D., Ph.D., FRCSC

Professor, Department of Surgery, University of Alberta

Wed Jan 17, 2018 (1-4PM)

Clinical cell therapy for the treatment of diabetes and the view from a transplant recipient

*plus public lecture Jan 17 (7-8PM)

Allen Eaves, M.D., Ph.D., FRCPC

Professor Emeritus, University of BC

President and CEO, STEMCELL Technologies, Vancouver

Terry Thomas, PhD

Chief Scientific Officer, STEMCELL Technologies

Wed Jan 24, 2018 (1-4PM)

An introduction to the largest biotech company in Canada, focused on the supply of reagents for stem cell research

Denis Claude Roy, MD

Professor, University of Montreal, CEO CellCAN Regenerative Medicine and Cell Therapy Network

Wed Jan 31, 2018 (1-4PM)

CellCAN: a network of Canada’s main cell therapy centres and description of the inner workings of GMP facilities for cell manufacturing

*plus public lecture Jan 31 (7-8PM) 

Peter Zandstra, Ph.D., FRSC

Chief Science Officer, Centre for the Commercialization of Regenerative Medicine (CCRM)

Professor, University of BC

Wed Feb 7, 2018 (1-4PM)

Scaling things up; design of bioprocesses for the growth and differentiation of stem cells

An introduction to CCRM

Michael Rudnicki, Ph.D., FRSC

Senior Scientist, Ottawa Hospital Research Institute, Scientific Director, Stem Cell Network (SCN), Ottawa

Wed Feb 28, 2018 (1-4PM)

SCN: A network of more than 50 Canadian PIs and a catalyst for Canadian stem cell research

*plus public lecture Feb 28 (7-8PM)

Megan Levings, Ph.D.

Investigator, BC Children’s Hospital Professor, Department of Surgery, University of BC

Wed Mar 7, 2018 (1-4PM)

Cell therapy to control immune homeostasis; from basic science to clinical trials

Timothy Caulfield, LL.B., LL.M.

Professor, Faculty of Law and School of Public Health, University of Alberta

Thur Mar 15, 2018 (1-4PM)

Ethical aspects of using stem cells and genetic engineering, stem cell tourism

*plus public lecture Mar 15 (7-8PM)

Cheryl Gregory- Evans, Ph.D.

Professor, Department Ophthalmology and Visual Sciences

University of BC

Wed Mar 21, 2018 (1-4PM)

Eye development and therapy for congenital eye disease

Knut Woltjen, Ph.D.

Associate Professor

The Center for iPS Cell Research and Application (CiRA), Kyoto University

Wed Mar 28, 2018 (1-4PM)

The development of induced pluripotent stem cells and emerging tools for genome editing

*plus public lecture Thur Mar 29 (7-8PM)

Timothy Kieffer, Ph.D.

Professor, University of BC

Course Coordinator

Wed Apr 4, 2018 (1-4PM)

Course wrap up, student presentations, course evaluation

Timothy Kieffer, Ph.D.

Professor, Department of Cellular and
Physiological Sciences, Department of Surgery
University of British Columbia
Vancouver, CANADA

Dr. Kieffer obtained his Ph.D. in the Department of Physiology at The University of British Columbia studying the release and metabolism of the gastrointestinal peptide glucose-dependent, insulinotropic polypeptide (GIP). He demonstrated that GIP and the related incretin hormone glucagon-like peptide-1 (GLP-1) are rapidly degraded in vivo by the enzyme dipeptidyl peptidase 4 (DPP4). Inhibitors of DPP4 are now used clinically to treat diabetes by prolonging the activity of GIP and GLP-1. He then conducted postdoctoral training at Harvard Medical School and Massachusetts General Hospital. He obtained his first faculty position at the University of Alberta, Department of Medicine, where he established his independent research focused on developing novel strategies to treat diabetes using gene- or cell-based approaches. One such approach developed by his lab involves engineering gut GIP-producing cells (K-cells) to produce insulin as a strategy for meal-dependent insulin replacement (published in Science). In 2000 he co-founded enGene, Inc., a private biotechnology company that is developing a gut gene delivery approach to treat metabolic diseases. In 2002, Dr. Kieffer joined the Departments of Cellular & Physiological Sciences and Surgery at UBC where he was promoted to Professor in 2007. A 10-year collaboration with Janssen Research and Development working on producing replacement beta cells from pluripotent stem cells resulted in several joint publications, including in Nature Biotechnology.

Dr. Kieffer has co-authored >155 peer reviewed publications on diabetes related topics in addition to several book chapters and patents. He has mentored >30 graduate students and postdoctoral fellows in addition to numerous undergraduates and is an active teacher. He has received scholarships from the Canadian Diabetes Association, the Alberta Heritage Foundation for Medical Research, the Michael Smith Foundation for Health Research, and JDRF, and his research has been supported by these agencies, in addition to the Canadian Institutes of Health Research, Canadian Foundation for Innovation and the Stem Cell Network. In 2010, he received the CDA Young Scientist Award. Dr. Kieffer has served as a consultant for several pharmaceutical companies and served on Editorial Boards for Physiological Reviews, the Canadian Journal of Diabetes and Islets. His laboratory continues to actively pursue novel approaches to treat diabetes.

 

Pamela Fayerman

Medical/Health Issues Reporter
The Vancouver Sun
Vancouver, CANADA

Pamela Fayerman has been the Vancouver Sun’s Health Issues reporter for 20 years. Her stories also appear in other Postmedia newspapers across Canada. She’s the recipient of numerous journalism awards and fellowships, from the New York Times Foundation, National Institutes of Health (U.S.A.), Association of Health Care Journalists, Canadian Institutes of Health Research, Canadian Medical Association, Knight Science Journalism, Jack Webster Foundation, Saskatchewan Press Club and Canadian Bar Association. She has a journalism degree from Ryerson University and has also completed courses at Queen’s University Law School; Columbia University (neuroscience); Mount Sinai Medical Centre (issues in aging); M.I.T. (medical evidence and digital science journalism); and Dartmouth College (Medicine in the Media). She’s a member of the Association of Health Care Journalists, Canadian Association of Journalists and the Canadian Science Writers Association. Pamela’s MedicineMatters website is the back story about people and events making health headlines.

James Shapiro, M.D., Ph.D., FRCSC

Professor, Department of Surgery
University of Alberta
Edmonton, CANADA

James Shapiro was born in Leeds, England, son of a family doctor. He studied Medicine in Newcastle and trained in Surgery in Bristol. He developed a longstanding interest in islet transplantation as a medical student. He has been on Faculty at the University of Alberta since 1998, where he now holds the Canada Research Chair in Transplantation Surgery and Regenerative Medicine. He directs the living donor liver transplant and the islet transplant programs in Edmonton. He was the lead investigator on the famous “Edmonton Protocol” cell transplant treatment for diabetes.

He is the Project 1 lead for the CNTRP, which is actively researching ex vivo organ transplant repair. In 2016, James and his team began first in human trials with embryonic stem cell derived insulin producing cells transplanted in an immunoisolation device, in partnership with ViaCyte Inc. James is the recipient of a Hunterian Medal from the Royal College of Surgeons of England, the Gold Medal in Surgery, is a Fellow of the Royal Society of Canada and a Fellow of the Canadian Academy of Health Sciences.

 

Allen Eaves, M.D., Ph.D., FRCPC

Professor Emeritus, University of British Columbia
President and CEO, STEMCELL Technologies
Vancouver, CANADA

Dr. Eaves, OBC MD PhD FRCPC, was the Founding Director of the Terry Fox Laboratory for Cancer Research (1981-06) and Head of Clinical Hematology at University of British Columbia (1985-2003). Currently Professor Emeritus of Hematology at UBC, he has devoted himself to building STEMCELL Technologies Inc, a company he founded in 1993 to provide standardized tissue culture reagents for regenerative medicine and those doing cancer and immunological research. Always profitable and with only 3% of its sales in Canada, STEMCELL is now Canada’s largest biotech company with over 1000 employees and a global network of sales offices and distribution centres serving thousands of customers.

Dr. Eaves has published over 200 papers in leading peer-review scientific journals. He has been elected as President of the International Society of Cell Therapy; President of the American Society of Blood and Marrow Transplantation; founding Treasurer of the Foundation for the Accreditation of Cell Therapy; and has been a Member of Health Canada’s Expert Working Group on the Safety of Organs and Tissues for Transplantation. He sits on the boards of The Canadian Stem Cell Network, The Canadian Stem Cell Foundation and The Centre for Commercialization of Regenerative Medicine. He is passionate about providing excellent tools and reagents for researchers and creating rewarding employment for those who love science.

 

Terry Thomas, Ph.D.

Chief Scientific Officer
STEMCELL Technologies
Vancouver, CANADA

Dr. Thomas completed her PhD in cell biology at UBC in 1983. Afterwards, she switched her research focus to stem cell biology and joined the Terry Fox Laboratories. There, she invented specific labeling reagents to enable purification of cells from mixed populations. One such technique was used in a Phase I clinical trial to deplete T cells from unrelated bone marrow grafts. Dr. Thomas joined STEMCELL Technologies in 1994 to head the Research and Development department. Under her leadership, R&D has grown from 2 to over 200 employees. Terry has 28 refereed journal publications, 11 book chapters and over 650 abstracts. She is a co-inventor of 14 patents and has negotiated 139 license agreements. Over the years, Terry has added corporate initiatives, corporate strategy and strategic marketing to her existing responsibilities of product development, intellectual property and licensing.

 

Denis Claude Roy, M.D.

Professor, University of Montreal
CEO, CellCAN Regenerative Medicine and Cell Therapy Network
Montreal, CANADA

Renowned researcher in hematopoietic stem cell transplant and executive committee member of the Canadian National Cancer Institute, Dr. Roy is Director of the Cellular Therapy Laboratory, scientific director at MRH and full professor at the Faculty of Medicine of the University of Montreal. He is also member of a working group on acute leukemia stem cell transplant, member of the Canadian Blood and Marrow Transplant Group and Clinical Trials and member of the Canadian Network on stem cell research. Dr. Roy did a postdoctoral fellowship in tumor immunology at the Dana-Farber Cancer Institute at Harvard University, USA and did his medical doctorate at University of Montreal. The aims of the studies performed at the laboratory are to use cellular and immunological approaches to fight such blood cancers as leukemia and lymphoma. The research unit is examining different monoclonal antibodies and immunoconjugates as well as a photodynamic approach for eliminating cancerous and alloreactive cells. The laboratory has also developed particular expertise in translational research, enabling the transfer of basic discoveries to patients. New hematological and immunological strategies have been identified and were implemented in early clinical studies (Phase 1 and 2). Dr. Roy’s laboratory is also the principal investigator of a multicentric study (Canada and USA) to evaluate a new photodynamic treatment. Dr. Roy is also working on the expansion of hematopoietic stem cells and blood cell progenitors that will enable and accelerate hematological and immunological reconstitution following transplantation. Dr. Roy is Kiadis Pharma’s (Netherlands) leading academic partner for the development of its blood cancer products and has collaborated with Kiadis Pharma for many years. Dr. Roy significantly contributed to the development of all ATIR™ blood cancer products, Reviroc™ and Rhitol™.

 

Peter Zandstra, Ph.D., FRSC

Chief Science Officer, Centre for the
Commercialization of Regenerative Medicine
Executive Director, Medicine by Design
Professor, University of British Columbia

Dr. Zandstra is a Professor at the University of Toronto’s Institute of Biomaterials and Biomedical Engineering, with a cross appointment in the Donnelly Centre for Cellular and Biomolecular Research and Chemical Engineering. In 2016, Dr. Zandstra was appointed University Professor, the highest academic rank at the University of Toronto. His research integrates engineering and biological approaches and in the last several years, work in his lab has focused on using computer modelling and strict control of the microenvironment (niche engineering) to develop a deeper understanding of the regulatory networks that determine stem cell fate. He has an h-index of 56 having published 215 papers that have been cited 10,863 times (Data from Web of Science – 03/10/2017).
Dr. Zandstra also serves as the Executive Director of Medicine by Design (MbD), and has co-founded three biotech companies. He is the Chief Scientific Officer at the Centre for Commercialization of Regenerative Medicine (CCRM), a Toronto-based regenerative medicine translation centre. In addition, he serves as the Scientific Founder and Chief Technology Officer for ExCellThera. This Canadian clinical stage cell therapy company focuses on development, manufacturing and distribution of expanded and genetically engineered hematopoietic stem cells for therapeutics treating blood diseases. Dr. Zandstra is the Canada Research Chair in Stem Cell Bioengineering and is the recipient of a number of awards and fellowships including the Premier’s Research Excellence Award (2002), the E.W.R. Steacie Memorial Fellowship (2006), the John Simon Guggenheim Memorial Foundation Fellowship (2007), the McLean Award (2009), and the Till and McCulloch Award (2013). Most recently he was the recipient of the 2017 Scale-Up and Manufacturing of Cell-Based Therapies Award from Engineering Conferences International. This prestigious award recognizes his outstanding contributions to the development and commercialization of stem cell-based therapies

 

Michael Rudnicki, OC, Ph.D., FRSC

Senior Scientist, Ottawa Hospital Research Institute
Scientific Director, Stem Cell Network (SCN)
Ottawa, CANADA

Dr. Michael Rudnicki is a Senior Scientist and the Director of the Regenerative Medicine Program and the Sprott Centre for Stem Cell Research at the Ottawa Hospital Research Institute. He is Professor in the Department of Medicine at the University of Ottawa. Dr. Rudnicki is CEO and Scientific Director of the Canadian Stem Cell Network (SCN). Dr. Rudnicki’s achievements have been recognized by numerous honours including being named a Tier 1 Canada Research Chair, an International Research Scholar of the Howard Hughes Medical Institute for two consecutive terms, a Fellow of the Royal Society of Canada, and an Officer of the Order of Canada.

Dr. Rudnicki is an internationally recognized thought leader in molecular genetics and regenerative medicine whose research has transformed our understanding of muscle development and regeneration, and fueled the development of novel molecular and stem cell based approaches to the treatment of muscular dystrophy and other neuromuscular disorders. Dr. Rudnicki’s key discovery was the identification and characterization of muscle stem cells. This work pivoted the field towards the study of adult regenerative myogenesis and set the stage for novel molecular and stem cell based approaches to the treatment of muscular dystrophy and other neuromuscular disorders. Dr. Rudnicki is a member of the editorial boards of Cell Stem Cell, Journal of Cell Biology, and Stem Cells. He is a founding Co-Editor-in-Chief of the journal Skeletal Muscle. Dr, Rudnicki has also organized many international research conferences and was a founding director of the Society for Muscle Biology.

For the past 12 years, Dr. Rudnicki has led the Stem Cell Network (SCN), a transformative initiative involving over 150 investigators across Canada, with a mandate to catalyze the translation of stem cell research into clinical applications, commercial products and public policy. As Scientific Director of the SCN, he has forged a national community that transformed stem cell research in Canada and brought research to the point where regenerative medicine is impacting clinical practice.

 

Megan Levings, Ph.D.

Investigator, BC Children’s Hospital
Professor, Department of Surgery
University of British Columbia
Vancouver, CANADA

Dr. Megan Levings has been in the UBC Department of Surgery since 2003 when she was recruited back to Canada as a Canada Research Chair in Transplantation. In 2011 she joined the BC Children’s Hospital Research Institute where she now heads the Childhood Diseases Theme. Dr. Levings’ scientific career started with summer research positions in a fruit fly genetics lab at Simon Fraser University. She then did her graduate training in the genetics program with Dr. John Schrader at UBC. In 1999 she joined Dr. Maria Grazia Roncarolo’s lab in Milan, Italy, undertaking postdoctoral training in the emerging area of immune regulation. She was among the first groups to show that a special kind of white blood cell, known as a T regulatory cell, could be used as a therapy to stop harmful immune responses. She continues this line of research at UBC, and is now internationally recognized in the field of human immunology and chairs the Federation of Clinical Immunology Societies Centres of Excellence. She leads a vibrant group of trainees and staff who are researching how to use T regulatory cells to replace conventional immunosuppression in the context of transplantation and autoimmunity.

 

Timothy Caulfield, LL.B., LL.M.

Professor, Faculty of Law and School of Public Health,
University of Alberta,
Edmonton, CANADA

Timothy Caulfield is a Canada Research Chair in Health Law and Policy, a Professor in the Faculty of Law and the School of Public Health at the University of Alberta and Research Director of the Health Law Institute at the University of Alberta. Over the past several years he has been involved in a variety of interdisciplinary research endeavours that have allowed him to publish over 300 academic articles. He is a Fellow of the Trudeau Foundation and the Principal Investigator for a number of large interdisciplinary projects that explore the ethical, legal and health policy issues associated with a range of topics, including stem cell research, genetics, patient safety, the prevention of chronic disease, obesity policy, the commercialization of research, complementary and alternative medicine and access to health care. Professor Caulfield is and has been involved with a number of national and international policy and research ethics committees. He has won numerous academic awards and is a Fellow of the Royal Society of Canada and the Canadian Academy of Health Sciences.  He writes frequently for the popular press and is the author of two recent national bestsellers: The Cure for Everything: Untangling the Twisted Messages about Health, Fitness and Happiness (Penguin 2012) and Is Gwyneth Paltrow Wrong About Everything?: When Celebrity Culture and Science Clash (Penguin 2015).

 

Cheryl Gregory-Evans, Ph.D.

Professor, Department of Ophthalmology
and Visual Sciences
University of British Columbia
Vancouver, CANADA

Dr. Gregory-Evans received an undergraduate degree in Pharmacology from the University of Sunderland, UK in 1985 and her PhD in Cell Biology from the University of Glasgow, UK in 1988. After completing postdoctoral research fellowships at the Jules Stein Eye Institute, UCLA Medical School in California, USA and at the Institute of Ophthalmology in London, UK she was appointed to the Faculty of Medicine at Imperial College London, UK before taking up her current position as Professor of Developmental Biology at the University of British Columbia in 2009. Her research focuses on understanding the molecular basis of human eye and craniofacial abnormalities, using zebrafish, mouse and lizard model systems. She has published over 90 research papers in the areas of mapping and identifying disease genes, ocular embryology, cancer xenograph models and developing novel therapeutic strategies, including most recently START therapy for aniridia. She has mentored 11 postdoctoral fellows, 12 PhD students, 4 MSc students and numerous undergraduate students.

 

Knut Woltjen, Ph. D.

Associate Professor
Center for iPS Cell Research and Application
Kyoto University
Kyoto, JAPAN

Dr. Woltjen obtained his B.Sc. Honors in Molecular Genetics from the University of Alberta (1998), and his Ph.D. in Biochemistry. and Molecular Biology (2006) from the University of Calgary, where he developed a gene-targeting vector construction method by recombination. During a postdoctoral fellowship in Medical Genetics in Toronto, he employed the piggyBac transposon in a novel approach to create induced pluripotent stem cell (iPS) cells, and served as Manager of the Ontario Human iPS Cell Facility. Dr. Woltjen joined Kyoto University’s Center for iPS Cell Research and Application (CiRA) in 2010, and in 2013 was cross-appointed to Kyoto University’s Hakubi Center for Advanced Research as an Associate Professor. Dr. Woltjen employs programmable nucleases in human iPS cells to study genetic variation in development and disease.


Please RSVP for all public lectures at eventbrite OR by email at regmedlecture@gmail.com
All public lectures will take place from 7PM to 8PM in the Life Sciences Centre at the UBC Main campus, 2350 Health Sciences Mall. Please enter through the west entrance.
Dr. James Shapiro Jan 17, 2018 Public Lecture video links:Part 1 of 2: https://youtu.be/dKDr0WGtW3Y
Part 2 of 2: https://youtu.be/pkuAA2MFXXQ
Dr. Denis Claude Roy Jan 31, 2018 Public Lecture video link: https://youtu.be/yYnFEERnxBA

Islet Transplantation and Stem Cells to Treat Diabetes

On January 17, 2018, Dr. James Shapiro, a professor and leader in transplant surgery at the University of Alberta, and Danielle Ciambrelli, an islet transplant recipient, visited the University of British Columbia to discuss the impact of islet transplantation on individuals with type 1 diabetes. The public lecture (see our Public Lectures page for video link) provided insight into the potentially overwhelming burden posed by type 1 diabetes, the ability for islet transplantation to treat the disease, and the future role of stem cell medicine in further improving treatment options.

The World Health Organization estimates that in 2014 there were 422 million people worldwide afflicted with diabetes, which is expected to become the seventh leading cause of death by 2030 [1]. Individuals with type 1 diabetes are unable to produce sufficient insulin due to their immune system attacking the insulin-producing cells of the pancreas (type 1 diabetes) or their body is resistant to insulin actions (type 2 diabetes). Insulin is the hormone which lowers blood sugar in the body when the levels are too high, and glucagon is the hormone which raises blood sugar in the body when sugar levels are too low. This is important, since if blood sugar is too high (hyperglycemia), complications such as long-term damage to the blood vessels in the eye may occur. Of greater concern in the short-term is dangerously low blood sugar (hypoglycemia), which can occur when too much insulin has been taken. The lack of sugar to power the brain and heart can lead to a patient entering a comatose state and even death. Individuals with type 1 diabetes in particular must monitor their blood sugar and administer insulin injections when needed to reduce blood sugar levels, and ingest sugar or administer glucagon when needed to quickly raise blood sugar.

The burden of continually managing diabetes extends further than following a regularly scheduled blood sugar monitoring routine. Individuals typically carry blood monitoring strips, insulin, emergency sources of sugar, and glucagon in case spontaneous hypoglycemic or hyperglycemic symptoms occur, no matter if at a sports practice, travelling abroad, or in the middle of an exam. Many parents of children with diabetes never receive a full night’s sleep to periodically monitor the child’s blood sugar. The New York Times video “Midnight Three & Six” reports on one child with diabetes whose mother awakes several times each night to check her child’s blood sugar in fear of deadly hypoglycemia during sleep. This highlights that diabetes is not only a physical burden to the child, but also a heavy psychological burden to their caretakers.

Several initiatives have been developed to address the burden of diabetes management. Nightscout is a project which uses an Android or iOS application to remotely connect to a glucose monitor. This allows remote monitoring which can ease the management of diabetes, such as allowing parents to observe their child’s glucose levels conveniently. In addition to remote monitoring, there are open-source prototypes developed for an “artificial pancreas”, such as one developed by OpenAPS, which is a low-cost device that detects blood sugar levels and automatically administers insulin correspondingly. This low-cost device is particularly impactful in low-resources settings where insulin pumps and blood sugar strips may be inaccessible. Both solutions demonstrate an integration of engineering and medicine, which highlights that collaboration can lead to impactful technologies developed by leveraging advances in each field.

Even with technologies for improving the insulin monitoring regimen, some individuals with type 1 diabetes may be unable to keep their blood sugar in control. Danielle Ciambrelli was one of these people and shared her story. Danielle was an athlete, competing at the national level in springboard and platform diving, when she was diagnosed with type 1 diabetes. Danielle’s athletic training already provided her with a strong discipline in managing her diet, monitoring her symptoms, and managing insulin injections, but her body still presented with erratic blood sugar levels at times. Many different insulin regimens were used, including pork insulin, synthetic insulin, multi-injections, and insulin pumps, but despite her discipline, Danielle was unable to find stability in her condition. Ultimately, Danielle decided to focus on her health and university studies, ready to manage a life with diabetes, until she underwent an islet transplantation under the Edmonton Protocol.

Dr. James Shapiro became a faculty member at the University of Alberta in 1998, practicing surgery while also conducting research in islet transplantation. In 2006, his team published the results of an international trial of an islet transplant technique called the Edmonton Protocol to treat type 1 diabetes [2]. The technique takes specially prepared pancreatic islet cells, which produce insulin and glucagon, from a donor pancreas and transplants them into the liver of a diabetic patient along with a special drug regimen to allow the islet cells to function in the new body. The goal is that the islet cells can now control blood sugar levels in the new body.

Danielle received her islet transplant in 2010 in Edmonton, and in the last seven years has not needed insulin injections nor has she suffered from episodes of severe hypoglycemia. Danielle is not the only patient to receive such benefits. Dr. Shapiro reports that in the last 17 years, over 2000 islet transplants have been conducted in 37 centres to treat type 1 diabetes. That number is expected to grow as more trials and training of new centres occur to improve the accessibility of this technique. Dr. Shapiro’s work highlights the value of pursuing research and development to solve difficult problems that ultimately advance the medical community’s understanding of treating a disease.

Dr. Shapiro emphasizes that islet transplantation is still very much a science in that, although results of insulin independence can be observed, there are many limitations and potential opportunities to improve the treatment. Not all patients of the Edmonton Protocol achieve insulin-independence and Dr. Shapiro is investigating different body locations and methods to place the islet cells, such as in the stomach. Dr. Shapiro also notes that, even if islet transplantation from a donor pancreas is perfected, only 0.0009% of all individuals with diabetes can receive an islet transplant due to the limited number of donors. Certainly, the technique will continue to help patients such as Danielle, but there is a need for methods that can treat many more patients.

Stem cell technology provides a potential treatment option, as stem cells can develop into islet cells. Stem cells address the issue of the limited number of pancreatic islet donors, as one embryo, which may already have been marked for disposal in an in-vitro fertilization clinic, could theoretically be used to generate enough islet cells to treat everyone in the world living with diabetes. Dr. Shapiro highlighted work by Dr. Timothy Kieffer’s group at the University of British Columbia, which used a seven-stage protocol that developed embryonic stem cells into insulin producing cells in a laboratory [3]. The insulin producing cells can potentially function similarly to islet cells and help control blood sugar levels if they are transplanted into a human body. These advancements aim to be implemented in clinical trials in the future to use stem cells as a viable source of islet precursor cells for individuals with diabetes.

Dr. Shapiro’s group is also investigating techniques to improve the survivability of transplanted islet precursor cells derived from stem cells. In one approach, a narrow nylon tube is placed under the skin for around a month, which allows blood vessels to form around the tube. The tube is then removed and islet precursor cells derived from stem cells are placed in the emptied location with accessible blood vessels to improve the health of the cells [4]. Currently, Dr. Shapiro’s group observes the ability for the cells to control sugar levels when tested in the laboratory, and Dr. Shapiro hopes that the technique can be transferred to the clinic in the future to improve the success rate of treating diabetes with islet implantation. Similar to the Edmonton Protocol, any technique involving stem cells requires rigorous testing and development before being applied. With further research, the strengths and limitations of stem cell technologies can be identified which will advance our understanding of stem cells as a treatment option for diabetes.

An impactful message that the students received while learning about Dr. Shapiro’s investigation is the potential of combining research, development, and clinical application. Rigorous scientific study with many collaborators was required to evolve islet transplantation from a laboratory investigation to the technique it is today. This includes clearly defining requirements for succeeding or failing insulin independence, repeating the tests in multiple trials, and transparently presenting limitations to identify what can be improved. Research initiatives such as the development of an artificial pancreas, a minimally-cumbersome glucose monitoring system, and the integrating of stem cell technology are all key steps in developing better treatment options to improve the lives of future patients, similar to how the Edmonton Protocol has done.

About The Authors:

Ricky Hu is a student in the Master’s of Applied Science program at the University of British Columbia. He received his Bachelor’s of Applied Science degree in Engineering Physics at the University of British Columbia and is now conducting research in medical imaging segmentation to improve early diagnostic techniques for insidious disorders such as liver cancer and preeclampsia.

Avineet Randhawa is a student in the Master’s of Engineering program at the University of British Columbia. He received his Bachelor’s of Applied Science degree in Chemical Engineering at the University of Toronto and is in the Engineers in Scrubs program to work on collaborative projects between engineering students and surgeons to solve clinical problems.

[1] Mathers, C. D. Projections of Global Mortality and Burden of Disease from 2002 to 2030. PLoS Medicine 3 (2006).

[2] Shapiro, A. M. J. et al. International Trial of the Edmonton Protocol for Islet Transplantation. The New England Journal of Medicine 355, 1318-1330 (2007).

[3] Rezania, A. et al. Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells. Nature Biotechnology 32, 1121-1133 (2014).

[4] Pepper, A. R. et al. Transplantation of Human Pancreatic Endoderm Cells Reverses Diabetes Post Transplantation in a Prevascularized Subcutaneous Site. Stem Cell Reports 8, 1689-1700 (2017).

 

 


Organoid Technology and the Role of STEMCELL Technologies in Supporting this Research

On January 24th, 2018, the University of British Columbia hosted two former members of the UBC community from STEMCELL Technologies: Dr. Allen Eaves (President and CEO) and Dr. Terry Thomas (Chief Scientific Officer). During their visit, they both discussed very fascinating stories about the journey of STEMCELL Technologies from an “in-home biotech start-up” (as Dr. Eaves calls it) to the biggest Canadian biotech company with multiple locations around the world.

In 1993, after being unsatisfied with the quality of available cell culture media, Dr. Eaves began to make his own cell culture media and sell it to some colleagues; the demand for his standardized and cost-effective media has increased incredibly. STEMCELL Technologies was established in Vancouver, BC to support the advancement of cell biology scientific research. Since then, supplying high quality, innovative reagents, tools and services, STEMCELL Technologies scientists have helped life sciences researchers around the world. Today STEMCELL Technologies has more than 1000 employees, around 350 of which are PhD/master’s degree holders, and sells more than 2000 products. In addition to the headquarter unit in Vancouver, STEMCELL Technologies has 10 other locations (3 in North America, 3 in Europe and 4 in Asia and Oceania) to provide local product and technical support. As of 2017, the US is the largest market for STEMCELL Technologies products with around 62%, while the Canadian market with only 4% of annual sale is ranked after China and Europe.

One of the novel research areas that has received extensive attention world-wide is the very fast-growing area of 3D organoids. STEMCELL Technologies has recently launched several reagents and tools to help this research field. Organoids are small 3D structures resembling the organ they are representing. They are not designed to replace a damaged organ in the human body as the technology required for developing fully functional organs still lies far in the future. However, being an organized group of tissue-specific cells, they can recapitulate several different key features of organs, they offer a highly robust and scalable platform for researchers to study a wide range of subjects, and they express the biochemical pathways and genetic information of the source [1].

One of the main applications of organoid technology so far has been the study of developmental processes in human organs. For many researchers, human development research has been a mystery. Madeline Lancaster, one of the pioneers of the brain organoid field, has a great analogy for this situation: “The lack of access to human organs for the fundamental development questions for researchers is like a kid with a very sophisticated spacecraft toy who is asked to figure out the working mechanism of the toy without touching it.” So now, these 3D assemblies of the cells, providing a physiologically relevant model, can be used to study different aspects of developmental biology in humans.

A typical organoid protocol starts with an isolated stem cell population. Then, a supportive proteinaceous structure called Matrigel®, that allows the organoids to develop into more complex tissue, is often required. After a set period of time when the organoid starts growing larger, equipment that will allow media agitation in the organoid environment is required to enhance nutrient and oxygen exchange in the media, and let the organoids grow larger. Then, if required, they can be placed in animals to allow them to further develop the organ structure and architecture. Finally, the fully developed organoids are removed and examined for the particular structures of interest within the organ they represent.

All around the world, researchers are studying cellular composition, tissue formation and mechanisms associated with malfunction of different organs using organoid technology. For example, incorporating many of the physiologically relevant features of the in vivo intestinal tissue, “mini guts” are powerful tools to understand gastrointestinal development. One of the main applications of these organoids is to study the intestinal epithelial layer (a layer similar to a strand of a shag carpet which is responsible for nutrient absorption in the intestine), how it is formed and constantly renewed and how it is affected in the case of a disease. In combination with other experimental techniques including genetic manipulation, the organoid-based models can serve as a platform for drug screening as well as patient-specific drug administration. STEMCELL Technologies recently launched IntestiCult™ Organoid Growth Media, which are complete growth media supporting the establishment, expansion and long term maintenance of intestinal organoid cultures. The “mini-guts” generated using this complete and refined medium retain the structure and all main cell types of adult intestinal epithelium. Therefore, the intestinal organoid field is now ready to move to research applications including disease modeling, tissue regeneration as well as drug screening [2].

Another example of well-established organoids are brain organoids, or “mini-brains”, which are used to study early brain development as well as the molecular mechanisms involved in neurological diseases such as autism, Parkinson’s and Alzheimer’s disease. These 3D stem cell-derived culture systems include several different organ-specific cells and incorporate spatial organization similar to brain and exhibit some of the key functions of it. STEMCELL Technologies recently launched the STEMdiff™ Cerebral Organoid Kit, which enables robust and efficient establishment and maturation of human brain organoids. These organoids, to a great extent, capture the complexity of the human brain in terms of the cellular organization, composition, and heterogeneity of the brain structure and, using some external chemicals, the model can form different regions of the human brain (for example midbrain, hypothalamus or forebrain) [3].

Other organoids, such as liver, heart and lung, are just beginning to be explored. STEMCELL Technologies has recently started the quality control procedure of specialized media to grow heart organoids. Although the field of organoid research is maturing rapidly, perhaps the biggest caveat to organoid technology, similar to other 3D cell culture models, is its limited reproducibility. Before organoids can be extensively used for drug and toxicity screening or other high-throughput testing, the reproducibility issue needs to be addressed.

Although still in its infancy and quite expensive to develop (~$150 / organoid), organoid technology shows how cells interact with their surrounding environment. Given a suitable environment and ingredients, the cells (to some extent) rearrange themselves in a spatial organization similar to tissues and communicate with each other as they would do in the body. Organoid systems extensively improve laboratory-based cell biology research compared to 2D cell culture platforms. However, there are still some concerns to be addressed about this novel technology, including questions about reproducibility, timing and media formulation for consistent observations world-wide. STEMCELL Technologies’ mission for providing very high quality media components to a great extent addresses these concerns, which in turn translate to reproducibility of the growth, establishment, expansion and long-term maintenance of organoid cultures and provides researchers with a platform to focus on vascularization within the organoids or heterogeneity of the tissues and perhaps enables large scale manufacturing of the organoid systems in the near future.

About the Author:

Roza V Ghaemi is a PhD student in the biomedical engineering program at the University of British Columbia. She received her Master’s of Applied Science degree in biomedical engineering at the University of British Columbia and graduated as an Engineers in Scrubs fellow. Now her research is focused on using organoid technology to study neurodegenerative diseases and in particular Alzheimer’s disease.

References:

  1. STEMCELL Technologies Inc. (2017). Organoid Information Hub. Retrieved from https://www.stemcell.com/discover-organoids.
  2. STEMCELL Technologies Inc. (2017). Intestinal organoids. Retrieved from https://www.stemcell.com/technical-resources/area-of-interest/organoid-research/intestinal-research/overview.html
  3. STEMCELL Technologies Inc. (2017). Neural organoids. Retrieved from https://www.stemcell.com/technical-resources/area-of-interest/organoid-research/neural-organoids/overview.html



 

 

 

 

 

 

 

 

 

 

 

 

 


Cellular Therapies and their Potential to Cure Cancer

On January 31, 2018, Dr. Denis Claude Roy, a renowned researcher in the field of hematopoietic stem cell transplants, visited the University of British Columbia. Dr. Roy is the Director of Research for CIUSSS East of Montreal, Scientific Director for the Centre of Excellence for Cellular Therapy at Hopital Maisonneuve-Rosemont, CEO of CellCAN, and a Professor of Medicine at the University of Montreal. Over the course of his career, Dr. Roy has been involved in numerous clinical trials involving transplant of hematopoietic stem cells to treat cancer. During his visit, Dr. Roy discussed the process of bringing promising cellular therapies from the bench to clinical trials.

For many patients with blood cancers such as leukemia or lymphoma, hematopoietic stem cell transplants provide an option for a cure. Hematopoietic stem cells are found in the bone marrow and give rise to blood cells including immune cells. Patients are treated with chemotherapy or radiation to kill cancer cells. However, these chemotherapy doses are also detrimental to a patient’s bone marrow and blood cells. A stem cell transplant provides the patient with new stem cells, which repopulate the immune system following chemotherapy and attack any remaining cancer cells.

Hematopoietic stem cells used for transplant may be autologous (the patient’s own cells) or allogeneic (cells from another individual). However, both of these sources have limitations. With an autologous transplant, there is a risk of re-introducing the cancer. With an allogeneic transplant, there is a risk that immune cells within the transplant will recognize the recipient as foreign, causing graft-versus-host disease (where the transplanted cells mount an immune response against the recipient) if the donor and recipient are not correctly matched.

Dr. Roy’s work focuses on the challenge of eliminating problematic cells from hematopoietic stem cells prior to transplantation. He has developed methods to eliminate cancer cells within an autologous transplant or immune cells within an allogeneic transplant that have the potential to attack the recipient, without harming the stem cells.

One such method is ATIR101, which is licensed by Kiadis Pharma. In this method, T cells (lymphocytes that participate in cellular immunity) are administered with the hematopoietic stem cell transplant. It can take months for the transplanted patient to recover normal immune cell functions from the stem cell transplant. During this time, they are at risk for infections as well as relapse of their cancer. If the transplanted stem cells are administered with donor T cells, these T cells can protect the patient against infections and cancer relapse immediately. The T cells are treated prior to administration to remove any cells that could potentially cause graft-versus-host disease. This method has been tested in Phase I/II clinical trials, in which 67% of high-risk patients treated with this therapy survived for at least 5 years. These patients had a low incidence of infection and low relapse rate. These trial results have shown this to be a safe and effective therapy, which improves survival for patients with these cancers.

Dr. Roy also gave a public lecture during his visit at UBC, discussing the progression from allogeneic hematopoietic cell transplantation to more promising, rigorous studies in cell and immune therapy for malignancy. All further efforts in cancer immunotherapy aim to be as selective as possible by targeting only cancer cells, while trying to avoid immune responses of transplanted stem cells against the recipient. For this purpose, minor histocompatibility (a state in which the absence of immunologic interference or a state of immunologic similarity which enable the transplanted graft/tissue to be accepted and functional) antigens can be used for more targeted and enhanced immunotherapy. Minor histocompatibility antigens (MIHA) are small polymorphic peptides that are found on the cell surface. Since small amino acid differences can be detected by T cells, MIHAs can be used as targets for cancer immunotherapy. In this method, T cells are collected from a donor for formation of targetable MIHAs with ex vivo vaccination with leukemia antigens. After in vitro (occurring in a laboratory environment) expansion, MIHA-specific T cells being more selective towards to cancer cells are injected to the recipients.

Another significant development in cancer immunotherapy is chimeric antigen receptor T cell (CAR T) therapy. Chimeric antigen receptors are genetically engineered receptors, and as such provide an opportunity to design a therapy in which the power of a patient’s own immune system can be harnessed to eliminate cancer cells. On July 2014, the Food and Drug Administration (FDA) approved a CAR T cell therapy for B cell acute lymphoblastic leukemia that began at the University of Pennsylvania in 2012. B cell acute lymphoblastic leukemia is one of the most common cancer diseases diagnosed in children. CD19 is an antigen expressed specifically on B cells, making it an ideal target to treat B cell malignancies. For this therapy, T cells are genetically modified to express a protein receptor which allows them to target CD19 to eliminate cancer cells. The clinical trial was conducted with a total of 30 children and adults receiving CTL019 at Children’s Hospital of Philadelphia and the Hospital of the University of Pennsylvania. Ninety percent of the patients who received CD19-targeted CTL019 therapy had achieved complete response; however, 25 percent of those who achieved complete response subsequently relapsed. Although CAR T cell therapy is a recently emerging approach, it has great potential to improve cancer immunotherapy.

During his lecture, Dr. Roy revealed how difficult it is to move from devastating, conventional cancer treatments like chemotherapy and radiotherapy to cancer immunotherapy or other cell therapies, despite the promising results of these studies. Industrialization of cellular therapies requires different considerations to be taken into account. There are regulations and guidelines implemented by governmental organizations such as Health Canada or the FDA to conduct a fair clinical study. These guidelines include regulations starting from preliminary pre-clinical studies to clinical trials. Aside from its scientific challenges, cellular or immunotherapy must be scalable and economical for its successful commercialization. For instance, Novartis, that also contributed to the clinical trial at the University of Pennsylvania, set the price at $475,000 for a single infusion for their CAR T cell therapy (1). Yescarta, another cancer immunotherapy using CAR T cells, from Kite Pharma/Gilead Science, was approved by the FDA in October 2017. Gilead Science listed the price at $373,000 for each patient (2). Thus, Dr. Roy drew attention to the importance of the industrialization of cellular and immunotherapies by considering the number of patients who may potentially benefit from these breakthrough developments.

Dr. Roy provided the audience with the opportunity to understand and appreciate what the future holds in cellular therapy and how engineering and clinical medicine are integrated. Last but not least, he emphasized how crucial it is to move forward from the scientific studies to clinical trials and real life circumstances. With the contribution of stem cell studies and advances in bioengineering technology, these excellent achievements in the field of cell therapy, which include using either a patient’s own immune system or donated T-cells, bring hope that curing cancer may be possible in the near future.

About the Authors:

Katie MacDonald is a MASc student in the Biomedical Engineering program at the University of British Columbia. She received a Bachelor of Engineering Degree in Chemical Engineering from McGill University. Her research focuses on optimizing the expansion of thymus-derived regulatory T cells, with the goal of developing standard methods for large-scale expansion that would enable a study to test whether these suppressive cells can reduce graft-versus-host disease following hematopoietic stem cell transplant.

Cagri Kocyigit is a Master of Applied Science student in Biomedical Engineering Program, at the University of British Columbia. He holds a Master of Science degree in Chemistry from Ankara University. Now, his research is focused on islet cell encapsulation for type-1 diabetes to avoid inflammatory response to transplanted islet cells.

References:
(1) http://www.onclive.com/web-exclusives/novartis-sets-a-price-of-475000-for-car-tcell-therapy, accessed on February 2, 2018.
(2) https://www.reuters.com/article/us-gilead-sciences-fda/fda-approves-gilead-cancer-gene-therapy-price-set-at-373000-idUSKBN1CN35H , accessed on February 4, 2018.


The opportunities, process and manufacturability of stem cell therapy products

On February 7th 2018, Dr. Peter W. Zandstra, a professor at the University of British Columbia’s Institute of Biomaterials and Biomedical Engineering, visited our class at the University of British Columbia. Dr. Zandstra is a man of “many hats”, as noted by Dr. Kieffer, referring to his numerous accolades and contributions to the world of bioengineering in Canada. Dr. Zandstra is the co-founder of three biotech companies and holder of a Canada Research Chair in stem cell bioengineering. The Zandstra lab focuses on regeneration of tissues and development, and utilization of tools to modulate stem cell responses.

Cell therapy, in general terms, is a therapy which involves cellular materials, usually living cells, implanted into a patient. These cell therapies are being developed to treat a wide range of diseases and hence being made into products. Cell therapy products can also be made from the patient’s own tissue to have certain properties by manipulation and culture and injected back into the patient [1].

Dr. Zandstra’s research spans two topics: first, how cells make decisions, and second, how engineering fundamentals can accelerate the development of therapies or help understand how cells make decisions. He addresses this by stating that “the problem that we all face is becoming increasingly good at measuring gene regulatory networks, genetic information, single cell information at this level. However, we have a very poor understanding as to how this relates to physiological and tissue organ function.” How this challenge is being dealt with is by both controlling and understanding how these regulatory networks are influenced by the environment that occurs during tissue development and ultimately affects tissue function.
There are different types of stem cells. There are totipotent stem cells, that can give rise to any cell type or a complete embryo, pluripotent, that are embryonic stem cells, and multipotent, that are adult stem cells. Stem cell type is important for when you start thinking about how you will manufacture these cells because the solutions used to manufacture these cells are very different. There are several things we can do with stem cells: you can understand the biology of a disease better, you can use cells to develop better drugs, and manufacture them into a uniform and consistent cell – based model.

When it comes to controlling cell behaviour, there are two main tools that can be used. One is by “niche engineering”, which is engineering the environment around the cell to control cell fate. The second way is by engineering the cell itself, and programming the cell to perform the tasks that we provide. A lot of bioengineering has traditionally been in engineering the niche environment. In niche engineering there are many tools that can be used, such as bioreactors to control the environment, materials to stimulate the niche (can be synthetic or natural) and mathematical models to predict complex interactions, by interpreting overwhelming information and aiding in designing improvements.
Aside from the science behind stem cell therapy, if we believe that cell therapies in regenerative medicine are a great opportunity, then the question is how these cells can be manufactured for therapeutics. As of today, there are three companies that have approval to make T-cells for specific types of cancer in Canada: Novartis, Kite Pharma, and Celletis/Service. For the number of patients per year, they will need to manufacture about 10,000-11,000 batches of T-cells for T-cell therapeutics annually. Hence, these companies are strategizing how they can decrease the cost of manufacturing, build facilities that are appropriate for commercial manufacturing, and develop models for autologous therapies that comply with health care distribution and profit perspective.
Dr. Zandstra explained the challenges of achieving stem cell products with high quality during the manufacturing process. Because of the biological complexity of cells, it is difficult to deal with numerous issues, from the incomplete understanding of cellular mechanisms to variabilities in starting materials and product features.

To tackle these problems, Dr. Zandstra introduced quality-by-design principles [2]. Quality-by-design is a process which was initially developed in Japan, to assist their automatic manufacturing sector. In the late 1980s to early 1990s, it was adopted by the pharmaceutical industry for drug development. The US Food and Drug Administration (FDA) has been using it as a metric to assess pharmaceuticals and biologics. Recently, this concept is being considered for medicine formulation, including cell therapy manufacturing. Briefly, the quality-by-design process contains different steps that manufacturers can go through when they are thinking about how to optimize manufacturing process.

The first step is to define the quality target product profile and critical quality attributes. Quality target product profile indicates the properties of the end products desired for clinical use, and critical quality attributes are those properties that ensure product quality. For manufacturing cell therapy products, the quality target product profile could contain identity, purity, potency, dose, and karyotype. Among overall profiles, identity, purity, and potency are critical quality attributes which essentially drive the design space of the system. For example, cell products can be identified by testing cell surface markers to ensure the right phenotypes of cells. As for qualified purity, the manufacturer must achieve the required cell dose while minimizing off-target cell types and other material levels. Cell therapy products must also function appropriately in patients as demonstrated by both in vitro and in vivo functional assays.

Dr. Zandstra showed an interesting example to illustrate the application of potency principle: when inducing immature stem cell into specific cardiac cells, one of the things that needs to be measured is force contraction of cells, because cardiomyocyte therapies are intended to act primarily through cell integration and replacement of contractile tissue mass. Dr. Zandstra also introduced Dr. Gordon Keller who is an expert in this area and has developed protocols for time-gated changes in the concentration of growth factors which affects the function of induced cardiac cells that can be used for clinical cell therapy [3].

The next step is identifying critical process parameters and material attributes that can affect critical quality attributes. Feeding strategy, pH, temperature, dissolved oxygen, agitation, and metabolites are general critical process parameters. Besides, specific-critical process parameters, including input cell quality and purity, cytokine activity, growth factor, and secreted factors, are also important for cell therapy products. Next, a control strategy should be developed to ensure critical process parameters and that materials attributes remain within the design space. Dr. Zandstra explained them to the class in a readily comprehensible way: “In a smart system, you must define design space so you can make small changes in your parameters and still have robust outcomes. In other words, if you suddenly change the type of bioreactor, the source of medium, or something else, you can still have some movements in critical quality attributes, which would still be within the design space. That is the key to success in cell therapy manufacturing…the control strategies make sure that you don’t deviate from the design space, or make sure you can still have acceptable viability”. He took inner-sensors of bioreactors as examples, which can control pH, dissolved oxygen, temperature etc., to explain how bioreactors respond to changes in critical process parameters based on feedbacks and the applicability of control strategies.

Dr. Zandstra said the traditional way of defining design space is using controlled experiments to identify the system response to inputs, but more and more attention focuses on system modeling. Large omics data sets provide a starting point for building reduced-parameter mechanistic models that link critical process parameters with critical quality attributes. Bioengineers can put more biological knowledge into this system by monitoring things based on their fundamental knowledge, such as signaling pathways, cytokine activity, metabolite biomarkers, and cell dynamic systems. However, few such models have been generated to date, and a lot of questions still need to be answered.

Overall, by better understanding both how genetic regulatory signaling networks control cell fate and the application of these principles, bioengineers would be able to manipulate the manufacturing process and achieve stem cell products with high quality for clinical trials.

In the end, Dr. Zandstra showed the class the pipeline of stem cell development (from basic research, manufacturing, clinical trial, product commercialization to therapeutic use of treatment) and suggested some published papers to students for further reading [4-6]. The Centre for commercialization and regenerative medicine (CCRM), which is led by Dr. Zandstra, is a non-profit organization that supports its partners in developing and commercializing cell and gene therapies and regenerative medicine technologies by providing both scientific and business services, and has been undertaking a lot of efforts in cell therapy field [7]. CCRM believes that cell therapy is an area where Canada can have a world leading role, that manufacturing will be the wedge, and that clinical development will directly provide benefits for patients.

References:
[1] Kim, InSoo. “A Brief Overview of Cell Therapy and Its Product.” J Korean Assoc Oral Maxillofac Srug, vol. 39, no. 5, Oct. 2013, pp. 201–202., doi:10.5125/jkaoms.2013.39.5.201. Kim, InSoo. “A Brief Overview of Cell Therapy and Its Product.” J Korean Assoc Oral Maxillofac Srug, vol. 39, no. 5, Oct. 2013, pp. 201–202., doi:10.5125/jkaoms.2013.39.5.201.
[2] Lipsitz YY, Timmins NE, Zandstra PW. Quality cell therapy manufacturing by design. Nat Biotechnol. 2016 Apr;34(4):393-400.
[3] Prowse AB, Timmins NE, Yau TM, Li RK, Weisel RD, Keller G, Zandstra PW. Transforming the promise of pluripotent stem cell-derived cardiomyocytes to a therapy: challenges and solutions for clinical trials. Can J Cardiol. 2014 Nov;30(11):1335-49.
[4] Csaszar E, Chen K, Caldwell J, Chan W, Zandstra PW. Real-time monitoring and control of soluble signaling factors enables enhanced progenitor cell outputs from human cord blood stem cell cultures. Biotechnol Bioeng. 2014 Jun;111(6):1258-64.
[5] Fares I, Chagraoui J, Gareau Y, Gingras S, Ruel R, Mayotte N, Csaszar E, Knapp DJ, Miller P, Ngom M, Imren S, Roy DC, Watts KL, Kiem HP, Herrington R, Iscove NN, Humphries RK, Eaves CJ, Cohen S, Marinier A, Zandstra PW, Sauvageau G. Cord blood expansion. Pyrimidoindole derivatives are agonists of human hematopoietic stem cell self-renewal. Science. 2014 Sep 19;345(6203):1509-12.
[6] Caldwell J, Wang W, Zandstra PW. Proportional-Integral-Derivative (PID) Control of Secreted Factors for Blood Stem Cell Culture. PLoS One. 2015 Sep 8;10(9):e0137392.
[7] https://ccrm.ca/cdmo-overview – accessed February 9th 2018

Other resources:
1. Centre for Commercialization of Regenerative Medicine (CCRM) https://ccrm.ca
2. Institute for Research in Immunology and Cancer — Commercialization of Research (IRICoR) https://www.iricor.ca
3. Dr. Peter Zandstra’s Lab http://stemcell.ibme.utoronto.ca/index.html
4. Dr. Gordon Keller’s introduction https://ccrm.ca/GordonKeller

About the Authors:

Sindhuja Krishnamoorthy received her Bachelors in science degree with a minor in biochemistry at the University of Texas at Arlington in Biomedical Engineering and is a graduate student in the Biomedical Engineering M.Eng professional program at the University of British Columbia.

Yuan Tian is a PhD student in Neuroscience program at the University of British Columbia. She received her Bachelor of Clinical Medicine from Sun Yat-sen University (Guangzhou, China), and a Master of Ophthalmology degree from Jinan University (Guangzhou, China). Her research will focus on stem cell therapy in the eye (retina), and explore the question: what kinds of methods could be used to help stem cells survive and better integrate into the recipient retina?


 

 

 


Follow us on twitter @regmedlecture