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.
PHYL 548B 002
Advanced Topics in Human Physiology: Stem Cells and Regenerative Medicine: What does the Future Hold?
Supported by Killam Connection Program
Professor, Department of Cellular & Physiological Sciences
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
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.
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.
- 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
Wed Jan 3, 2018 (1-4PM)
Course overview; the path from basic science to product development for cell based therapies
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.
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
Wed Apr 4, 2018 (1-4PM)
Course wrap up, student presentations, course evaluation
Professor, Department of Cellular and
Physiological Sciences, Department of Surgery
University of British Columbia
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.
Medical/Health Issues Reporter
The Vancouver Sun
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
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
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
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
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)
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
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,
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
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.
Center for iPS Cell Research and Application
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 firstname.lastname@example.org
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
Dr. Michael Rudnicki Feb 28, 2018 Public Lecture video link: https://youtu.be/54wHEee_om4
Dr. Knut Woltjen Mar 29, 2018 Public Lecture video link: https://youtu.be/Fu5m2oQdqK0
Islet Transplantation and Stem Cells to Treat Diabetes
Organoid Technology and the Role of STEMCELL Technologies in Supporting this Research
Cellular Therapies and their Potential to Cure Cancer
The Opportunities, Process and Manufacturability of Stem Cell Therapy Products
The Past, Present and Future of Stem Cells
Regulatory T Cell Therapies to Control and Regulate the Immune System
Hype Surrounding Stem Cells and Regenerative Medicine
Current Developments in Regenerative Medicine of Congenital Eye Diseases
The Future of Personalized Stem Cell Therapy using Genome Editing Tools
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 . 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 . 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 . 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 . 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.
 Mathers, C. D. Projections of Global Mortality and Burden of Disease from 2002 to 2030. PLoS Medicine 3 (2006).
 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).
 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).
 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).
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 .
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 .
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) .
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.
- STEMCELL Technologies Inc. (2017). Organoid Information Hub. Retrieved from https://www.stemcell.com/discover-organoids.
- STEMCELL Technologies Inc. (2017). Intestinal organoids. Retrieved from https://www.stemcell.com/technical-resources/area-of-interest/organoid-research/intestinal-research/overview.html
- STEMCELL Technologies Inc. (2017). Neural organoids. Retrieved from https://www.stemcell.com/technical-resources/area-of-interest/organoid-research/neural-organoids/overview.html
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.
(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.
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 .
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 . 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 .
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 . 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.
 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.
 Lipsitz YY, Timmins NE, Zandstra PW. Quality cell therapy manufacturing by design. Nat Biotechnol. 2016 Apr;34(4):393-400.
 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.
 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.
 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.
 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.
 https://ccrm.ca/cdmo-overview – accessed February 9th 2018
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?
On February 28th, 2018, Dr. Michael Rudnicki visited the University of British Columbia. He is a professor at the University of Ottawa, senior scientist at Ottawa Hospital Research Institute, and scientific director of the Stem Cell Network in Canada. In our class, Dr. Rudnicki introduced his own research about muscle stem cells in muscular dystrophies. His group has been studying in this field for many years to understand the underlying mechanisms and to explore stem cell therapies for these diseases. Skeletal muscles are voluntary muscles allowing us to conduct movements, such as walking or exercising. There are cells called “satellite cells” which are associated with mature muscle fibers in muscle tissues, and a portion of them are stem cells which are able to respond to damage. Under some conditions, these stem cells can enter the cell cycle and begin dividing, to produce renewed myofibers for repairing muscles.
Dr. Rudnicki’s research found that satellite stem cells can divide and generate committed progenitors through asymmetric division during development, and dystrophin gene expression is involved in the polarity of satellite stem cells. Patients with Duchenne muscular dystrophy, which is considered a rare type of muscular dystrophy, suffer from progressive skeletal muscle degeneration. These patients have mutations in the dystrophin gene, and as a result an inability to produce progenitors efficiently, promoting the progression of Duchenne muscular dystrophy. Dr. Rudnicki’s findings suggest the possibility that repairing satellite stem cells may be able to fix the genetic deficiency as a treatment for Duchenne muscular dystrophy. His group is also looking for drugs that can restore the asymmetric division by modulating satellite stem cells.
Dr. Rudnicki also gave a lecture entitled “Regenerative Medicine: The Potential of Stem Cells” to the public in the evening. After Canadian scientists Ernest McCulloch and James Till first discovered stem cells in bone marrow in 1963, a lot of progress has been achieved in stem cell research. To this day, Canada has an increasing number of leaders working in this area. Dr. Rudnicki introduced what stem cells are, how stem cells can be used, and the Stem Cell Network in Canada.
Stem cells can divide to make copies of themselves and give rise to specialized “differentiated” cell types that build up our bodies. Dr. Rudnicki presented a diagram showing the development of the fertilized egg, called a zygote, to demonstrate how embryonic stem cells develop into adult stem cells, and then mature into about 200 different cell types in our bodies. To be specific, embryonic stem cells, which are derived from the inner cell mass of the blastocyst, can give rise to the embryo. These cells gradually form the three germ layers that become more specialized and produce specific cell types, such as skeletal muscle cells or skin cells.
To demonstrate the tremendous potential of embryonic stem cells, Dr. Rudnicki briefly illustrated experiments that showed cultured embryonic stem cells can form all cell types in a chimeric mouse. After fertilization, an egg becomes a zygote and then a blastocyst. Embryonic stem cells are then obtained from the inner cell mass of blastocysts and put in a culture dish. After some time, they grow up as immortal cell lines and have many properties that are cancer-like, such as the ability to proliferate infinitely. Next, these cells are introduced into another blastocyst which is put into a female mouse. Thus, chimeric mice will be born with a mixture of cells from different blastocysts. If the host blastocyst is from a black mouse and the embryonic stem cells are from a brown mouse, the chimeric mice may have black and brown patches of hair.
Embryonic stem cells are pluripotent stem cells with diverse differentiation potential in the petri dish. From 1998, when human embryonic stem cells were first derived by Jamie Thomson, until now, researchers have been developing techniques to differentiate the cells to specific cell types, and more recently, to genetically modify them. As a result, particular cell types can be generated for transplantation in clinical trials of different diseases. Dr. Rudnicki said this was a revolutionary breakthrough which moved science forward. However, there are also a lot of concerns about the use of human embryonic stem cells such as safety (e.g. the potential formation of tumors), immune rejection, and the ethical use of human embryos for both research and clinical purposes.
Dr. Rudnicki then talked about induced pluripotent stem cells, created by Shinya Yamanaka and others in 2006. They took non-stem cell human skin fibroblasts and overexpressed four different genes that were found in embryonic stem cells. Under certain culture conditions, these fibroblasts were transformed into induced pluripotent stem cells, or iPSCs, which look similar to embryonic stem cells. Excitingly, iPSCs can be used in the same way as embryonic stem cells but they are patient-specific stem cells, thus avoiding immune rejection. This critical contribution was awarded the Nobel Prize in 2012.
It is worth mentioning that there are also adult stem cells in most organs throughout the human body: transplantation of a single blood stem cell into mice whose blood cells were destroyed rebuilt the entire blood system; brain stem cells give rise to progenitor cells which can turn into three types of cells, oligodendrocytes, astrocytes or neurons. Unlike embryonic stem cells, adult stem cells have restricted potential. Dr. Rudnicki introduced how these cells can be used therapeutically through numerous examples. For instance, bone marrow transplant for patients with leukemia or other blood cancers has been going on for over 40 years. Cord blood stem cells are isolated and expanded in a bioreactor for transplant use. Pancreas islet and spinal cord cell therapies include differentiation to specific cell types before replacement. In addition, genome editing by CRISPR-CAS is being applied in CAR T-cell therapy for cancer.
Dr. Rudnicki addressed some other potential applications of adult stem cells. He discussed drug specific stimulation of adult stem cells in tissues, which is able to enhance stem cell regeneration and correct disease deficiency. He also showed us how iPSCs can be used for developing personalized medicine approaches that are specific to genetic diseases: iPSCs from progeria patients can be differentiated into vascular smooth muscle and then used to screen drug libraries for compounds capable of reversing the accelerated aging associated with the disease. Another intriguing idea is using cancer stem cells to identify new drugs targeting stem cells over bulk tumor cells, which can lead to the degeneration of the tumor.
Last but not least, Dr. Rudnicki briefly showed us an overview of the Stem Cell Network  in Canada and the workable regulatory framework provided by CIHR guidelines to manage embryonic stem cell research . Dr. Rudnicki mentioned the concept of “Nuclear Cloning”, citing as an example the famous Dolly Sheep created by somatic cell nuclear transfer . Yet this fantastic technology has caused a lot of fears and controversies in the public, particularly among politicians. Using this technology to clone humans is illegal here in Canada. Although researchers should be aware of the hype around human stem cell research, Dr. Rudnicki believes that it has great potential to alleviate suffering in the future.
About the author:
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?
. Stem Cell Network: https://stemcellnetwork.ca.
. CIHR guidelines for stem cell research: http://www.cihr-irsc.gc.ca/e/15255.html.
. Campbell KH,cWhir J, Ritchie WA, Wilmut I. Sheep cloned by nuclear transfer from a cultured cell line. Nature. 1996 Mar 7;380(6569):64-6.
On March 8, 2018, Dr. Megan Levings, a professor at the University of British Columbia and investigator at BC Children’s Hospital, visited our class at the University of British Columbia. Dr. Levings’ research focuses on a subset of CD4+ T cells known as regulatory T cells. She discussed cell therapies to control immune homeostasis, focusing on these regulatory T cells.
Dr. Levings began with a general background on cell therapies. The most successful cell therapy to date has been haematopoietic stem cell transplantation, more commonly known as bone marrow transplantation. This procedure, first successfully performed in 1968, is used to treat several blood cancers and immune system disorders. As opposed to traditional pharmaceuticals, cell therapies are designed to treat the cause of the disorder, not the symptoms, and to provide long-term protection.
Dr. Levings described some of the more specialized cell therapies being developed using regulatory T cells. Regulatory T cells are different than other immune cells in that they suppress immune system responses, and are responsible for maintaining the balance between tolerance and immune responses.
There are 2 types of tolerance, central and peripheral. Central tolerance, which develops in the thymus for T cells, prevents the body’s immune system from attacking the body’s own antigens. This is important for the prevention of autoimmune diseases. On the other hand, peripheral tolerance mainly controls responses to foreign antigens such as food. Dr. Levings described how regulatory T cell therapy can be used to manipulate immune tolerance to treat or prevent disease. As an example, regulatory T cells could be infused into a patient during an organ transplant in order to prevent graft rejection, which occurs when the patient’s immune system attacks the new organ. This is currently under investigation in clinical trials (1).
Regulatory T cells may be obtained from a patient’s blood, umbilical cord blood, or from the discarded thymus of an infant undergoing open heart surgery (2). Most studies in the field thus far have used regulatory T cells isolated from the patient’s own blood. The cells are then manipulated in the laboratory to expand the number of cells and enhance their functionality, before being reintroduced into the same patient in an attempt to achieve a therapeutic benefit.
Dr. Levings’ own research is focused on assessing the safety and effectiveness of regulatory T cells as therapeutic agents for stem cells transplants, organ transplants, and autoimmunity. However, unlike most previous research, Dr. Levings aims to use cells isolated from discarded infant thymuses instead of from blood. The major advantage of this method is that the thymus yields a vastly greater number of regulatory T cells than blood samples, making it significantly easier to expand the cells to the very large numbers that are required for therapeutic use.
Most studies in the field thus far have used polyclonal regulatory T cells, that is, cells that are broadly suppressive to the immune system and do not react in a specific manner to an antigen. Dr. Levings aims to use alloantigen-specific regulatory T cells, which are engineered to target specific immune responses in the body. Alloantigen-specific regulatory T cells have 2 advantages over polyclonal regulatory T cells. Fewer cells are required to achieve the same level of immune suppression towards the target antigen, because the cells are more specific. Also, they do not cause broad immune suppression, and so they do not increase the susceptibility to opportunistic infections as much as polyclonal regulatory T cells.
In a further effort to make the target recognition of regulatory T cells more specific to the antigen of interest, Dr. Levings explained that the cells are being genetically engineered with chimeric antigen receptors (CARs) (3). In particular, mouse models have been developed to test the effectiveness of antigen-specific regulatory CAR T cells. A small portion of skin taken from one mouse (which has an HLA-A2+ genetic phenotype) is implanted into another mouse (which has an HLA-A2- genetic phenotype). Naturally, the recipient mouse’s immune system rejects the donor skin graft due to the HLA incompatibility. To address this incompatibility, regulatory CAR T cells engineered with an HLA-A2+ tolerant phenotype are infused into the recipient mouse. Preliminary results indicate that these regulatory T cells do indeed localize to the region of the skin graft, while leaving the rest of the mouse’s immune system relatively untouched.
Dr. Levings described that further control of the cells can be achieved by engineering them to produce markers that promote localization to a certain region of the body. A recent advancement in this area was to create regulatory T cells that express retinoic acid, a metabolite of vitamin A, which targeted the cells to the intestine after they were infused into mice.
Dr. Levings said there are still challenges ahead, however, to bring regulatory T cell therapies to the clinic. For example, it is difficult to manipulate regulatory T cells in a good manufacturing practice (GMP) facility, and sources of cells are still limited (4). It is also possible the cells may interfere with protective immune responses, leading to an increased risk of infections and cancer. The survival and distribution of the cells after infusion also need to be further studied to determine the long term effects of the treatments. Nevertheless, Dr. Levings described how the future looks bright for the next generation of regulatory T cell therapies. With a combination of methods to make the cells more specific to their target, and to engineer a mechanism to target the cells to the intended region of action in the body, scientists such as Dr. Levings hope to create finely controlled regulatory T cell therapies which will be effective in the treatment of disease, and improve quality of life for patients.
About the Authors:
Sepehr Kamal is a MSc student in the Genome Science and Technology Program at the University of British Columbia. He holds a BSc degree in Biology from the University of British Columbia. His research is focused on pancreatic beta-cell development and stem cell therapies for diabetes.
Shreyas Rangan holds Master’s degrees in Biotechnology and in Genome Science, and is currently pursuing a PhD in the Biomedical Engineering program at the University of British Columbia. His research interests focus on using Raman spectroscopy as a non-invasive, non-destructive tool to study the state of cells being modified for use in various therapeutic and industrial applications.
(2) Dijke IE, et al. Discarded Human Thymus Is a Novel Source of Stable and Long-Lived Therapeutic Regulatory T Cells. Am J Transplant. 2016 Jan;16(1):58-71.
(3) MacDonald K, et al. Alloantigen-specific regulatory T cells generated with a chimeric antigen receptor. J Clin Invest. 2016;126(4):1413-1424.
(4) Trzonkowski P, et al. Hurdles in therapy with regulatory T cells. Sci Transl Med. 2015 Sept;304ps18304ps18.
On March 14, 2018, Timothy Caulfield joined our class to discuss the issues and ‘hype’ surrounding stem cells and regenerative medicine, followed by a public lecture titled: Twisted Messages, False Hope and Unproven Regenerative Therapies. Caulfield is both a Professor in the Faculty of Law and the School of Public Health and the Research Director of the Human Law Institute at the University of Alberta. He also holds a Canada Research Chair in Health Law and Policy. Caulfield’s work focuses on health policy and the spread of scientific misinformation. Over his career, he has authored over 350 academic manuscripts and has published several national bestsellers. He has a strong presence on social media, with nearly 30,000 Twitter followers (@CaulfieldTim).
There has been a lot of talk about stem cells in the media recently – they are being marketed as a cure for joint pain, aging, blindness, Parkinson’s disease, and more. They can be used to regrow organs, and can even be used to treat your pets! But what exactly are stem cells? In the developing embryo, stem cells are signaled to differentiate into all the cells that make up a living organism. In an adult, some stem cells still exist on stand-by, and may be activated to replace damaged cells. The use of stem cells for the treatment of disabilities is slowly gaining momentum, but currently only a handful of legitimate treatments exist. These include bone marrow transplants to treat cancer and some therapies to treat specific forms of blindness and burns.
At the moment, regulations surrounding stem cell clinics and treatments are minimal and differ between countries. Health Canada and the FDA currently assign these therapies with a drug designation, which allows certain clinics to bend the rules. For example, if a therapy can be labelled as “minimally manipulative”, regulations are more relaxed. This labelling is used to describe treatments involving the removal of tissues from a patient’s own body, the isolation of stem cell populations from that tissue, and the injection of these cells into various other locations of the same patient’s body. This can lead to dangerous results, such as the blinding of three patients in the USA who had cells injected back into their eyes as a treatment for their macular degeneration, or the death of a child in Germany after cells were injected into his brain. Some countries are beginning to pass specific legislation that covers the use of stem cells in regenerative medicine. In 2014, Japan updated their regulations to separately classify regenerative medicine products. However, this new legislation has caused some concern as it now allows companies to receive conditional market approval of their products while clinical trials continue through their later stages. China has also more recently introduced new legislation to crack down on the large number of stem cell clinics opening up in the country. These new laws require clinics to be registered with the health ministry, require studies to be performed at authorized hospitals, forbid clinics from charging patients during these trials, and forbid the advertising of these therapies.
“I’ve invested a lot of my career in stem cells. I believe this is a genuinely exciting area of research and we’re going to see real advances. I want those advances to come, but I’m worried about . . . the way people are portraying this,” says Caulfield. Unfortunately, amidst all of the ground-breaking and promising science is an equal amount of hype and nonsense, with people advertising false cures at a very high price. Caulfield suggests that part of the early hype surrounding stem cells may have arisen as a result of scientists attempting to combat the public’s ethical concerns about the emerging science, promising new treatments with inaccurate timelines to try and sway public perception. He now works to debunk many of the false claims involving stem cells and understand why people are so willing to believe the misinformation.
Why are the public so quick to believe these claims? Sometimes it is more than just a desperate final act by someone who is terminally ill. In the USA, the percentage of people who trust the healthcare system was down to 23% in 2014 . With physician distrust running so high, the public are turning to unregistered and unproven treatments rather than modern medicine. These unapproved therapies employ token tactics to seem more legitimate and “science-y”, such as publishing their research in predatory journals that are not peer-reviewed, citing early pre-clinical research to justify their clinical application without first studying the efficacy on humans, and receiving celebrity endorsements, which Caulfield has identified as particularly concerning. From magazine articles to twitter posts, the public are constantly exposed to celebrity opinions and endorsements. A recent study by Vosoughi et al. shows that false news is able to spread through social media much faster than the truth can, so these opinions can be spread across the internet with ease . Caulfield also talked about the mere-exposure effect, stating that “just being exposed to this noise makes you aware of it. And just being aware of it makes it seem more plausible.” For example, there has been an increase in the number of athletes receiving stem cell treatments to help them with joint and muscle injuries. The reporting of these treatments is moving away from the science and health columns of news outlets and into the sports pages. This means that the circulation of fake news by celebrities and mainstream media may be even more harmful than it appears.
So, how can we combat the hype? Part of the answer may lie in teaching critical thinking skills to the next generation and how to apply these skills to health information. This strategy has been shown to be effective for school-age children in Uganda, though long-term results have yet to be studied . Caulfield also believes that the regulatory bodies, such as Health Canada, could be playing a larger role in limiting the spread of false stem cell treatments. Finally, Caulfield closed his talk with a message for the scientists in the room: “I really think communication matters. I think we can all be part of the solution . . . Speak up, speak clearly, and really make the public know where the science is.”
A CBC article covering Tim Caulfield and his public seminar can be found at http://www.cbc.ca/beta/news/canada/british-columbia/debunking-stem-cell-myths-timothy-caulfield-1.4577631.
A Globe and Mail article by Tim Caulfield about the misuse of science in marketing can be found at https://www.theglobeandmail.com/opinion/in-2018-we-need-less-nonsense-and-more-science/article37514167/
 Blendon RJ, Benson JM, Joachim OH. Public trust in physicians – U.S. medicine in international perspective. N Engl J Med 2014; 371: 1570-1572.
 Vosoughi S, Roy D, Aral S. The spread of true and false news online. Science 2018; 359: 1146-1151.
 Nsangi A, Semakula D, Oxman AD, Austvoll-Dahlgren A, Oxman M, Rosenbaum S, Morelli A, Glenton C, Lewin S, Kaseje M, Chalmers I, Fretheim A, Ding Y, Sewankambo NK. Effects of the Informed Health Choices primary school intervention on the ability of children in Uganda to assess the reliability of claims about treatment effects: a cluster-randomized controlled trial. Lancet 2017; 390: 374-388.
About the Authors:
Shannon Sproul is an MSc student in Francis Lynn’s lab at the University of British Columbia, with an undergraduate degree in Biochemistry from the University of Guelph. Shannon’s research project is focussing on the development of pancreatic beta-cells from stem cells.
Mitchell Braam is a PhD student in Timothy Kieffer’s lab at the University of British Columbia. Mitchell’s research involves genetically engineering stem cells to probe genetic causes of diabetes.
On March 21st, 2018, we had the pleasure of receiving a presentation from Dr. Cheryl Gregory-Evans on her research on eye development and potential therapies for congenital eye diseases.
Dr. Gregory-Evans is a professor in the Department of Ophthalmology and Visual Science at the University of British Columbia. Her research focuses include the fusion of epithelia during eye development, ocular coloboma, and aniridia.
Dr. Gregory-Evans started by sharing her career path. She started in the UK where she obtained her PhD degree. Interestingly, eye research wasn’t her first choice. However, she was willing to take the opportunity, and her career turned out to be highly prolific.
Eye disease is an important public health issue. 600,000 Canadians (15% of the Canadian population) are registered blind. 60% of partially sighted or blind people are unable to work. Furthermore, 11.5 million Canadians at the age of 50 have a 1 in 285 chance to get age-related macular degeneration. Many of the eye diseases are heterogeneous in both the genetic changes causing the diseases and the severity of the diseases. Currently there is little to no treatment for many of the congenital eye diseases in humans.
At present, there are many ongoing ocular therapeutic trials. For example, replacement gene therapy improves patient condition by providing copies of genes lacking in the patients. This strategy is promising in recessive diseases. A well-known example of replacement gene therapy involving Leber congenital amaurosis, caused by deficiency in the gene RPE65. Unfortunately, although replacing RPE65 shows promising result in animal models, no long-term benefits were observed in humans due to inability to sustain expression of the introduced gene. Trials involving pharmaceuticals have also been conducted. As an example, valproic acid, a drug used as treatment for epilepsy, was trialed for treatment of hereditary retinal degeneration. Valproic acid can act as a molecular chaperone, molecules that aid protein folding. This property was hypothesized to be therapeutic for patients. However, it was found that it either had no effect or made the condition worse despite having promising pre-clinical results. This is due to the heterogeneity in the genetic mutations among patients, and the nature of the interaction between valproic acid and the mutated protein is dependent on the specific mutations presented. The two examples highlighted the complexity and the challenge of researches in eye diseases, and hint to a future with personalized medicine where the therapeutic intervention is dependent on detailed characterization of patient specific mutations.
Furthermore, Dr. Gregory-Evans introduced the class to a unique type of treatment, the bionic eye. In this example, they implanted a sensor array where degeneration of retina occurred. They found that the bionic eye improves macular degeneration in patient’s sight. This study will be further assessed with ten patients that will be monitored for a year. A visual representation of the effectiveness of this treatment was shown to the class from a video from BBC news (Link:
Dr. Gregory-Evans shared some of her research on a congenital disorder called aniridia. Aniridia is a condition where the iris of the eye is missing since birth. It is also associated with other conditions such as cataract, corneal disease, and foveal hypoplasia (abnormal cell growth in the fovea of the eye).
Dr. Gregory-Evans’ research in aniridia centered around a gene called PAX6. The PAX6 gene produces a type of protein called a transcription factor, proteins responsible for “turning on” other genes. Dr. Gregory-Evans is interested in understanding what PAX6 is turning on and why is it important for the development of the eye.
But how is PAX6 related to aniridia? It turns out that the majority of patients with congenital aniridia exhibit mutations in the PAX6 gene, in a way that causes the cellular machinery to produce a truncated dysfunctional protein. This is due to changes in the genetic sequence that normally encodes for the PAX6 protein, to a sequence that signals to “stop making protein”, or a stop codon. This type of mutation is call a nonsense mutation.
Dr. Gregory-Evans draw ideas from research in cystic fibrosis and Duchenne muscular dystrophy, diseases caused by the same type of mutations but in different genes, and discovered promising therapeutic strategy that may one day be used in human patients. In both cystic fibrosis and Duchenne muscular dystrophy, researchers and clinicians have experimented with a therapeutic strategy called nonsense suppression. This works by using a small molecule to induce a read through at the premature stop codon. Effectively, the cell ignores the stop signal in the genetic code that is caused by pathogenic mutations, and produces full-length and functional proteins.
Dr. Gregory-Evans applies the same idea to treat mice with aniridia. She used a small molecule that was used in trials aimed at patients with cystic fibrosis and Duchenne muscular dystrophy and applied it to mouse aniridia model that carries PAX6 mutation. She found that she can reverse the course of the disease and restore almost normal development of the eye of the offspring by intravenous injection of the drug to the pregnant mother mice. Remarkably, when she gave newborn mice the drug, she found that aniridia can also be treated. This informed her about the potential therapeutic window (a period when the treatment can be given to achieve desirable effects). She then further developed a formulation that can be applied directly onto the eye and deliver the drug to the vessel-less cornea as well as the rest of the eye. In collaboration with her husband, Dr. Kevin Gregory-Evans, she is now testing this treatment in human patients.
Dr. Gregory-Evans’ lecture was truly inspiring for future researchers in regenerative medicine. She highlighted some of the challenges faced by clinicians and researchers when trying to improve quality of life of patients. Her own research provided insights into the development of the eye as well as a potential new therapy for aniridia. It is inspiring to think that one day, we may be able to combat congenital diseases in highly ordered and complex organs such as the eye. However, it is very important for the public to learn about ongoing basic and translational research, as work like Dr. Gregory-Evans’ would not be a reality without public funding.
About the Authors:
Chien Chao is an MSc student in the Elizabeth J. Rideout lab at the University of British Columbia. His research is focused on sex differences in lipid storage using Drosophila as model.
Martin Kwok is currently an unclassified student at the University of British Columbia. He received a Bachelor of Engineering degree in Engineering Chemistry from Queen’s University.
Dr. Cheryl Gregory-Evans’ web page: http://ophthalmology.med.ubc.ca/person/cheryl-gregory-evans/
BBC: Bionic eye improves macular degeneration patient’s sight: http://www.bbc.com/news/av/health-33612558/bionic-eye-improves-macular-degeneration-patient-s-sight
On March 28 2018, Dr. Knut Woltjen, a high achieving associate professor and an expert in gene editing from the world-class stem cell research centre, CiRA (Centre for iPS Cell Research and Application, Kyoto University), visited our class from Japan to educate us on the history and current aspects of cutting-edge stem cell therapy. Dr. Woltjen discussed with the class how CiRA’s Nobel prize laureate, Dr. Shinya Yamanaka, revolutionized stem cell research with the invention of induced pluripotent stem cells (iPSCs) , and how gene editing can be applied on iPSCs to study diseases, or generate non-GMO crops that will provide billions of dollars of economical benefits, leading to the next era of medicine and agriculture.
Although Dr. Woltjen was visiting from Kyoto, Japan, he is actually a proud Canadian by birth and began his scientific career in Canada. Born in Alberta, Dr. Woltjen obtained his Bachelor of Science from the University of Alberta. Under the guidance of Dr. Derrick Rancourt in his graduate degree at the University of Calgary, he had the opportunity to travel to Kyushu University in Japan for a couple years to learn how to manipulate genes in mice. Thereafter, he obtained his PhD and became an expert in mouse genome modification. Later in his post-doctoral career at the University of Toronto, Dr. Woltjen famously developed a novel virus-free, footprint-free method to generate mouse and human induced pluripotent stem cells. This was a major breakthrough in the iPSC field because most methods at that time required the use of potentially carcinogenic viruses, and those virus vectors tend to leave behind traces of their own genetic information to the host cells they edited, potentially compromising the quality and safety of iPSCs. Dr. Woltjen successfully published his work in Nature scientific journal , which is one of the most prestigious publishers in the scientific community. His ingenious invention earned him a laboratory of his own at CiRA in 2010 when Dr. Yamanaka founded the institute.
Humbly quoting Sir Isaac Newton during his public lecture on March 29th: “If I have seen further it is by standing on the shoulders of Giants”, Dr. Woltjen acknowledged the work done by scientists before him for his success. It began from the discovery of DNA as the blueprint for life, to the invention of DNA sequencing, to the human genome project where scientists spent 15 years to sequence the entire human DNA content, to Dr. John Gurdon’s first successful somatic cell nuclear transfer, and the discovery of Dr. Yamanaka’s 4 genes for iPSC creation .
So what is an “iPSC”? What is so special about it that it won Dr. Shinya Yamanaka his 2012 Nobel prize in medicine? Dr. Woltjen explained the significance to us in the lecture. Life begins as one cell, the fertilized egg. This one cell divides repeatedly to generate more cells, that eventually begin to specialize and transform into different types of tissue. There are two main stages for stem cells. The first stage is before the cells in the fertilized egg become specialized, tissue-specific stem cells. At this stage, the stem cells are “pluripotent”, which means they remain super naive, and have the ability to turn into any type of tissue. These pluripotent stem cells are referred as embryonic stem cells (ES cells). After an ES cell has committed to its specialization fate, it becomes a “multipotent” stem cell, which is also known as a tissue progenitor cell. For example, an ES cell can become a multipotent neural stem cell or a multipotent muscle stem cell. These multipotent stem cells can only derive cells of that kind of tissue, which means a neural stem cell can generate all types of nervous tissue, but never muscle cells. Therefore, ES cells are the mother of all stem cells, and theoretically the most useful type of stem cell. However, there exists a dilemma. The embryo that gives rise to baby-you is destroyed when ES cells are harvested from it, so you would have never been born in the first place if your parents were to keep some ES cells for treating your future diseases. It is possible to use ES cells derived from other embryos, but the ethics of sacrificing another potential human life for medical use is greatly debated. Dr. Yamanaka recognized the problem and came up with a solution.
Since life begins with a single cell, and every cell in your body contains the same DNA, what if we can reverse the instructions cells received when they were specializing, and generate ES-like cells from an already-differentiated somatic cell such as skin cells? Dr. Yamanaka did exactly that. He found the four essential genes (Oct3/4, Sox2, Klf4, and c-Myc) that, when forcibly turned on, reverse the mature cell back into its embryonic, pluripotent form. He named these ES-like cells, induced pluripotent stem cells (iPSCs). When Dr. Yamanaka published his work in 2006, it took over the scientific society all over the world by storm . This literally means, when iPSC technology has been perfected, a healthy human could theoretically infinitely replenish their aged cells and organs using their own, stored single-aliquot of iPSCs. For Dr. Woltjen and his colleagues, iPSCs opened up a new way to study and potentially cure genetic diseases. Instead of injecting viruses or other vectors into the body to repair disease-causing genes, one could make an iPSC from the patient, modify the genetic information outside the body in a lab, grow a disease-free organ from it, and transplant it back into the patient!
Later in the second half of his lecture, Dr. Woltjen stated his appreciation for the strong support from CiRA, Kyoto University, as the institute provides the finest research environment in the world to study iPSCs, from its fundamental mechanism to translational applications. Dr. Woltjen then emphasised that although we have the technology to build genetic disease models or drug screening platforms using iPSC technology, in order to treat the patients, we still need to correct the disease-causing genes at a molecular level before transfusing the regenerative cells back into patients. With the revolutionary breakthroughs in gene editing technology in this decade, Dr. Woltjen recognized its promising value in gene therapy and cell-based therapy.
First, Dr. Woltjen introduced to us the precise gene editing technologies such as Zinc-finger nucleases (ZFNs), Transcription activator-like effector nucleases (TALEN), and CRISPR/Cas9. For example, TALEN acts like a molecular scissor that binds to specific sites of the gene locus with the engineered DNA binding domains, and creates a cleavage at the targeted site of the defective gene. It then tricks the cell’s natural DNA repair machinery to suppress or replace the defective gene with a normal gene introduced by the scientist.
Dr. Woltjen also mentioned that the design and synthesis of TALEN or ZFN protein DNA binding domains requires an extensive amount of experience in molecular biology, and it is gradually outcompeted by the simpler and more powerful CRISPR/Cas9 technology, where you only need to design a simple 20 nucleotide guiding RNA that allows multiple targeting on the genome at the same time. More specifically, the CRISPR/Cas9 gene editing vector consists of a guiding RNA (sgRNA) sequence and a Cas9 endonuclease protein sequence that gets transfected and transcripted in host cells. The sgRNA recognizes and binds to the target sequence of the host gene that is followed by a protospacer adjacent motif (PAM) sequence, guiding the Cas9 protein to cut the host gene exactly 3 nucleotides away from the PAM sequence. The repair of the DNA cleavage usually undergoes either non-homologous end joining (NHEJ) or Homology Directed Repair (HDR) and allows insertion/deletion (indel) mutations to happen . Dr. Woltjen also pointed out that this technology still has to overcome major issues such as the safety and efficiency of CRISPR/Cas vector delivery, immune responses from the host body, as well as the potential of off-target effects in both ex vivo and in vivo editing.
Dr. Woltjen then introduced to us several gene editing therapy cases. One patient with a rare metabolic disorder Hunter syndrome, an X chromosome linked genetic disease, was treated by infusing ZFNs to repair the malfunctioning gene ; ZFN was also used in a clinical trial to remove the CCR5 gene of CD4 T cell to create HIV resistance . The gene editing technology also opens the door to gene therapy treatment of many future single nucleotide polymorphism (SNP) diseases such as sickle-cell anemia, β-thalassemia, and cystic fibrosis.
Last but not least, Dr. Woltjen presented the development of a single base modification method from his lab that was published early this month (March 2018) in Nature Communications. His lab has developed a CRISPR/Cas9 gene editing method to insert an endogenous sequence containing a template using microhomology-mediated end joining (MMEJ) pathway that importantly allows the gene modification without introducing undesired sequences such as LoxP or PiggyBac , a so-called “scarless” approach. Dr. Woltjen closed his speech by saying that collaboration (both domestic and international) is the most important and efficient factor to advance science in the field of iPSC research and the field of genetic engineering.
About the authors:
Sammy Zheng is a MSc student in the Faculty of Pharmaceutical Sciences at the University of British Columbia. He completed his BSc degree in Pharmaceutical Chemistry from the University of Toronto. He’s now studying the pharmacokinetics of immune-boosting agent carrying nanoparticles in mice model.
Peter Fan is a MSc student studying Neuroscience in the Faculty of Medicine at the University of British Columbia. He completed his BSc degree in Biochemistry also at UBC. Inspired by Dr. Yamanaka’s work, he is currently researching ways of transforming cells of the scar tissue in spinal cord injury patients into functional neurons using transcription factor induced reprogramming.
Video link for Dr. Woltjen’s public lecture: https://www.youtube.com/watch?v=Fu5m2oQdqK0
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