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Cells: from Robert Hooke to Cell Therapy – a 350 year journey

Scientific meeting








The Royal Society, London, 6-9 Carlton House Terrace, London, SW1Y 5AG


Scientific discussion meeting organised by Professor Sir Ian Wilmut FRS, Professor Johan Hyllner and Professor Chris Mason

Neural stem cells. Copyright © the Cell Therapy Catapult Limited and ReNeuron Limited 2014.

Event details

The importance of cellular structure was first recognised by the British scientist Robert Hooke and described in Micrographia (Royal Society, September 1665). In this meeting, world-leading researchers will describe the way in which new approaches to cell therapy are being provided by our progressively greater understanding of the biology of cells, in particular different populations of stem cells.

The meeting programme can be downloaded here.

A theme issue of Philosophical Transactions B  has been published in association with this meeting. 

Attending this event

This event is intended for researchers in relevant fields and is free to attend. There are a limited number of places and registration is essential. An optional lunch is offered and should be booked during registration (all major credit cards accepted).

Enquiries: Contact the events team

Event organisers

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Schedule of talks

05 October


Session 1: From cells to the identification of stem cell populations in adult tissues and embryos

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Professor Roger Pedersen, University of Cambridge, UK

09:05-09:35 Robert Hooke, microscopy, and the cell in early science

Dr Felicity Henderson, University of Exeter, UK


In 1665 Robert Hooke published Micrographia, the world's first fully-illustrated book of microscopy, and revealed to his readers a completely new world. Along with images of insect, mineral and plant specimens he included a section of cork, describing the tiny box-like structures he observed as 'cells'. Although he did not understand their biological function fully, he attributed to them some of the properties of cork such as buoyancy. 

In Micrographia, Hooke had two goals: to present his observations, and to persuade his readers that scientific research had the potential to improve people’s lives. Hooke made a point of linking his observations with his readers’ experiences of everyday life – for example, including an enormous image of a louse clinging to a human hair, rather than simply showing the insect alone on the page. By investigating the microscopic world, Hooke hoped to understand the mechanisms and structures of nature and perhaps make use of them in his own instruments and inventions. This talk will show that Hooke’s microscopic research underpinned his theories of the natural world, including his conviction that fossils were the remains of once-living plants or animals, a theory that would only be widely accepted over a century after Hooke’s death.

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09:50-10:20 Evolution of Normal and Neoplastic Tissue Stem Cells

Professor Irving Weissman, Stanford University, USA


The transition from single cell species to multicellular organisms led to organ and tissue development, which has resulted in the emergence of specialized cells that self-renew as well as differentiate, called stem cells. Following embryonic development, most tissues and organs are continuously regenerated from tissue/organ specific stem cells. In most tissues only the primitive stem cells self-renew. Within a tissue, stem cells may be diverse, and subject to stem cell competition for their niche. Both germline stem cell and somatic stem cell competition in species as diverse as colonial protochordates and humans have been documented. Stem cell isolation and transplantation is the basis for regenerative medicine. Self-renewal is dangerous, and therefore strictly regulated. Poorly regulated self-renewal can lead to the genesis of cancer stem cells, the only self-renewing cells in the tumor. Dr Weissman and colleagues have followed the progression from hematopoietic stem cells (HSCs) to myelogenous leukemias. It was found that the preleukemic clones progress at the stage of HSCs, from which emerge “leukemia” stem cell at an oligolineage downstream stage that has evaded programmed cell death [PCD] and programmed cell removal [PrCR], that self-renews.  In early chronic myeloid leukemia, bcr-abl+ HSC clones outcompete normal HSCs. The transition from the chronic phase to myeloid blast crisis results in the leukemia stem cells appearing in the granulocyte-macrophage progenitor (GMP) stage. While there are many ways to defeat PCD and senescence, there appears to be one dominant method to avoid PrCR—the expression of cell surface “don’t eat me” CD47, the ligand for macrophage SIRPα. All cancers tested express CD47 to overcome expression of “eat me” signals such as calreticulin. Antibodies that block the CD47–SIRPα interaction enable phagocytosis and killing of the tumor cells in vitro and in vivo. All tested human cancers are susceptible to phagocytosis in the presence of anti-CD47 blocking antibodies, which are in clinical trials.

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11:05-11:35 Neural stem cells: their role in brain development, maintenance and potential nervous system therapies

Dr Sally Temple, Neural Steme Cell Institute, USA


The central nervous system (CNS) is the most complex of tissues, with hundreds of types of neurons and glia patterned into unique regions, connected through intricate, complex circuits. Developmental studies have shown that the initial plate of neuroepithelial cells is regionally patterned by morphogenic signals. This areal identity is then interpreted by neural stem cells and more restricted precursor cells, collectively called neural progenitor cells (NPCs), to produce the diverse cells of each CNS region. Progeny arise from NPCs on a defined schedule, and migrate to their final position. The birthdate of each cell type is precise for a given species, but varies widely, e.g. from mice to men.  

Studies of these developmental events have revealed numerous classes of NPCs. Some are present just through the developmental period, others are retained in active stem cell zones throughout life. Notably, in the hippocampal dentate gyrus, stem cells continually make new neurons that contribute to memory formation. Adult progenitors capable of producing oligodendrocytes and astrocytes are also present widely in the CNS.

Neurodegenerative diseases typically attack specific CNS populations, for example, the hippocampal stem cell system in Alzheimer’s Disease, and midbrain dopaminergic neurons in Parkinson’s disease. Traumatic damage can cause loss of numerous cell types. Human NPCs are being harnessed to replace the lost cells and are already in clinical trials. In addition, the fact that progenitor cells are present in the adult CNS offers the exciting opportunity for stimulating endogenous reparative processes, reawakening the inner salamander.

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11:50-12:20 Somatic cell nuclear transfer: origins, the present position and future opportunities

Professor Sir Ian Wilmut FRS, MRC Centre for Regenerative Medicine, UK


Nuclear transfer involves the transfer of the nucleus from a donor cell into an egg from which the chromosomes have been removed was considered first as a means of assessing changes during development in the ability of the nucleus to control development. In 1996 a nucleus from an adult cell controlled development to term of Dolly the sheep. She was the first adult clone derived by transfer of a nucleus from an adult cell. The new procedure has been used to target precise genetic changes into livestock; however, the greatest inheritance of the Dolly experiment was to make biologists think differently. If unknown factors in the recipient egg could “reprogramme” the nucleus to a stage very early in development then there must be other ways of making similar changes. Within 10 years two laboratories showed that the introduction of selected proteins changed some of the cells to stem cells equivalent to those derived from an embryo. This ability is providing revolutionary new opportunities in research and cell therapy.

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12:35-13:35 Lunch


Session 2: Demonstrations of developmental plasticity in mammalian cells

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Professor Fiona Watt FMedSci FRS, King's College London, UK

13:35-14:05 Present and future challenges of pluripotent stem cells

Dr Kazutoshi Takahashi, Gladstone Institute, USA


The old is going destiny for us. However mature differentiated cells making up our body can be rejuvenated to embryo-like fate called pluripotency which is an ability to differentiate into all cell types by enforced expression of defined transcription factors. The discovery of this induced pluripotent stem cell (iPSC) technology has opened up unprecedented opportunities in regenerative medicine, disease modeling and drug discovery. In this talk, Dr Takahashi will introduce the process leading to iPSC technology, applications and future perspectives of human iPSCs. And, also show that how iPSC technology has evolved along the way.

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14:20-14:50 Direct reprogramming towards the neural lineage

Dr Marius Wernig, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, USA


Cellular differentiation and lineage commitment are considered robust and irreversible processes during development. Challenging this view, we found that expression of only three neural lineage-specific transcription factors Ascl1, Myt1l, and Brn2 could directly convert mouse fibroblasts into functional in vitro. These induced neuronal (iN) cells expressed multiple neuron-specific proteins, generated action potentials, and formed functional synapses. Thus, iN cells are bona fide functional neurons. Addition of a fourth transcription factor Neurod1 also enabled reprogramming of human fibroblasts.

Completely unexpectedly, the iN cell reprogramming process is substantially more efficient and faster than reprogramming to pluripotent stem cells. By investigating the mechanism of action of the transcription factors involved, we found a molecular explanation for this discrepancy. We found that Ascl1, one of the key driving iN cell transcription factors, is not only a pioneering factor in the sense that it can bind nucleosomal DNA in the fibroblast chromatin context, but we observed it  bound to its physiological targets two days after infection in mouse fibroblasts as defined as targets in neural stem and progenitor cells. The three main iPS cell reprogramming factors Oct4, Sox2, and Klf4, on the other hand, have been shown to bind nucleosomal DNA but mostly bind ectopic genomic sites that are typically not bound by them in ES cells. Thus, the specific properties of the transcription factors used for reprogramming and their interaction with the chromatin appear to determine the reprogramming dynamics and efficiency between reprogramming systems. We also found that expression of neuronal lineage determining factors in human ES and iPS cells yields functionally mature neurons of unprecedentedly speed. These “ES-iN cells” are in quality almost equivalent to a primary neuronal culture and we have shown to be useful to study synaptic phenotypes of disease-associated mutations.

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15:30-16:00 Naive pluirpotency

Professor Austin Smith, FRS, FRSE, Wellcome Trust – Medical Research Council, Cambridge Stem Cell Institute, University of Cambridge

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16:15-16:45 Human pluripotent stem cells: the new "patient"?

Professor Christine Mummery, Leiden University Medical Center, The Netherlands


Derivation of many different cell types from human pluripotent stem cells (embryonic stem cells or HESCs and induced pluripotent stem cells or hiPS cells) is an area of growing interest both for potential cell therapy and as a platform for drug discovery and toxicity. Most particularly, the recent availability of methods to introduce specific disease mutations into human pluripotent stem cells and/or to derive these cells as hiPS cells by reprogramming from any patient of choice, are creating unprecedented opportunities to create disease models “ in a dish” and study ways to treat it or slow down its rate of development. Understanding the underlying developmental mechanisms that control differentiation of pluripotent cells to their derivatives and mimicking these in defined culture conditions in vitro is now essential for moving the field forward. Professor Mummery and colleagues have used these methods to produce isogenic pairs of hiPSC lines to compare diseased and corresponding control cardiomyocytes and vascular endothelial cells and identify disease related phenotypes and mechanisms. The use of isogenic pairs has proved crucial since variability between “healthy control” hiPSC lines is often greater than the difference between a diseased cells and its isogenic control. Drug responses of hESC-derived cardiomyocytes to a variety of cardiac and non-cardiac drugs were examined and shown that iPSC derived cardiomyocytes with mutations in ion channel genes can accurately predict changes in cardiac electrical properties and reveal drug sensitivities also observed in patients.

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06 October


Session 3: Established and recent cell therapies

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Professor Johan Hyllner, Cell Therapy Catapult, UK

09:00-09:30 Discoveries and execution of the first specialised cell therapy (autologous chondrocytes) in global use

Professor Anders Lindahl, The Sahlgrenska Academy, University of Gothenburg, Sweden


Cartilage injuries and the subsequent osteoarthritis (OA) disease have been an enigma for doctors since the age of Hippocrates.  OA is characterized by cartilage degradation, formation of osteophytes and subchondral sclerosis that leads to joint destruction and severe impairment of mobility. OA is one of the most common forms of musculo-skeletal disease throughout the world with over 80 million patient affected and nearly 1 million patients are hospitalized each year in the U.S alone with a cost estimated to $60 billion. Currently no early diagnostic marker is available and no disease modifying treatment exists except for autologous chondrocyte transplantation (ACT) originally developed by our group. These facts are still a challenge for today’s cartilage research and were the driving force behind the development of the autologous chondrocyte transplantation technique in Gothenburg Sweden in the 1980s. The interdisciplinary collaboration and events leading to the first transplantation and its successful spread worldwide will be discussed and the clinical long term outcome after ACT will be presented. Furthermore, the scientific knowledge in cartilage regeneration and stem cell fields has increased as reflected by the significant increment in publications in the field. The cellular focus in the transplantation technology has revealed new understanding of the degenerative OA disease where we now have implications that the disease is basically a cell regenerative dysregulation and not a consequence of wear and tear. Future aspects of the treatment including the use of matrices and potentially new cellular concepts will also be discussed.

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09:40-10:10 Cellular transplantation of human islets or stem cell progenitors in the treatment of diabetes

Professor James Shapiro, University of Alberta, Canada


Transplantation of islets into the portal vein of patients with Type 1 diabetes is a safe and highly effective therapy to eliminate hypoglycaemia, and stabilise glucose control. The downside is that the treatment relies on a scarce cell source (human organ donors), and lifetime immunosuppression is needed. The process of extracting islets in GMP facilities requires considerable expertise, and is not universally available. The original Edmonton Protocol series (NEJM 2000) led to high rates of one-year insulin independence in a small number of patients. Most returned to insulin therapy at low dose by 3 to 5 years. Recent further advances in clinical islet transplantation have been substantial, and now at least 6 centres report insulin independence rates of over 50% at 5 years with T-depletional immunosuppression combined with anti-inflammatory antibodies. A large Phase 3 trial in North America will likely lead to imminent Biological Licensure for islet transplantation in the US.

Human embryonic stem cell derived progenitors proffer a potential limitless source of islet precursors for further differentiate in vivo. These may be transplanted within immunoisolating membranes to ‘shield’ against allo and autoimmune attack. This approach is currently undergoing early pilot safety and feasibility investigation as part of first-in-human clinical trials. Rigorous safety trials are underway to define and mitigate these risks. 

Thus, islet transplantation provides a glimpse of the future potential of cellular transplantation in diabetes. Successful embryonic stem cell derived progenitors will potentially open up the market exponentially, provided early trials demonstrate safety and efficacy.

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10:20-10:50 Treatment of Parkinson’s disease using cell transplantation

Professor Olle Lindvall, Lund University, Sweden


In Parkinson’s disease (PD), the main pathology underlying motor symptoms is a loss of nigrostriatal dopaminergic neurons. Clinical trials with intrastriatal transplantation of human fetal mesencephalic tissue have shown that the grafted dopaminergic neurons reinnervate the striatum, restore striatal dopamine release and, in some cases, induce major, long-lasting improvement of motor function. However, non-motor symtoms originating from degeneration outside striatum or in non-dopaminergic systems are not alleviated by intrastriatal implantation of dopaminergic neurons. Stem cells and reprogrammed cells could potentially be used to produce dopaminergic neurons for transplantation in PD patients. Recent studies demonstrate that dopaminergic neurons of the correct substantia nigra phenotype can be generated from human embryonic stem cells in large numbers and standardized preparations, and are soon ready for patient application. Also dopaminergic neurons derived from human induced pluripotent stem cells are being considered for clinical translation. Important challenges will be to demonstrate the potency (growth capacity and functional efficacy) and safety of the generated dopaminergic neurons in preclinical animal models. The dopaminergic neurons should then be tested, using optimal patient selection and cell preparation and transplantation procedures, in controlled clinical studies.

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11:30-12:00 Pioneering industrialisation of cell based therapies

Professor Silviu Itescu, Mesoblast, Australia

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12:10-13:15 Lunch


Session 4: Novel cell therapies

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Professor Chris Mason, UCL, UK

13:15-13:45 Stem cell approaches to treat cardiovascular diseases

Professor Philippe Menasche, Department of Cardiovascular Surgery, Hôpital Européen Georges Pompidou, Paris


Stem cell-based therapy is currently tested in several trials of both acute myocardial infarction and chronic heart failure. While the striking efficacy of early revascularization may question the rationale for an additional cell-based therapy in patients with an acute infarction, the situation is dramatically different for chronic heart failure when patients, the number of whom is escalating, have exhausted conventional treatments and are not candidates for more invasive procedures like cardiac transplantation or implantation of a mechanical assist device. The main question then is to determine how experimental data can be translated into clinical practice. To meet this objective, it is critical to more thoroughly decipher the mechanism of action of the transplanted cells and, more specifically, to validate the currently prevailing hypothesis that these cells fail to rebuild a myocardial tissue by themselves but rather act by harnessing endogenous repair pathways. Namely, the confirmation of this mechanism would have three major clinically relevant consequences: (1) the choice of the optimal cell type, based of head-to-head comparisons of the functional effects of secretomes derived from different cell types, although the already available comparisons clearly favor the use of cardiac-committed cells; (2) the optimization of early cell retention and survival, rather than of sustained cell engraftment, so that the cells reside in the target tissue long enough to deliver the factors underpinning their action, and (3) the reliance on banked, fully qualified allogeneic cells, the expected rejection of which should only have to be delayed since a permanent engraftment would no longer be the objective. One step further, the long term objective of cell therapy could be to use the cells as biofactories exclusively exploited for producing factors and then to only administer them to the patient along with controlled release delivery systems. The whole production process, including manufacturing, quality controls, regulation and costs, would then be closer to that of a biological pharmaceutic, thereby raising the hope of a facilitated and thus expended clinical use.

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13:55-14:25 Fine-tuned T cell receptors for cancer immunotherapy

Dr Bent Jakobsen, Adaptimmune Limited, UK


Human tumours are known to express unique antigens; however tumour immune evasion mechanisms often prevent effective naturally occurring anti-tumour immune responses. Adoptive T cell therapy, in which T Cell Receptors are engineered to identify cancer tumour antigens with increased affinity, is emerging as a promising strategy for the treatment of many forms of cancer, including those with historically bleak outcomes.

Dr Jakobsen and colleagues have developed methods to engineer naturally occurring TCRs and enhance their ability to target and bind to cancer peptides thereby enabling a highly targeted immunotherapy. Unlike current antibody based therapies, affinity enhanced TCRs are able to target a larger pool of intracellular antigens presented on the cell surface as short peptides bound to human leukocyte antigen (HLA). This capability significantly increases the breath of targets, particularly as intracellular targets are known to be more closely associated with cancer.

Target identification and validation, together with a broad and robust preclinical safety testing strategy are critical in the development of affinity-enhanced TCRs.  Engineering TCRs requires balancing the need for higher affinity to the target peptide with the risk of cross-reactivity, which increases at higher affinities. Safety considerations include both on-target (antigens expression in normal tissues in addition to tumour) and off-tumour toxicity (recognition of other antigens). 

NY-ESO-1 is a cancer antigen which is expressed at high frequency (>30%) in a range of cancers including ovarian, prostate, NSCLC, myeloma, bladder, melanoma, oesophageal and breast. Affinity-enhanced TCRs have been developed to target NY-ESO-1. T cells transduced with affinity enhanced TCRs to NY-ESO are currently in clinical trials for synovial sarcoma, multiple myeloma, melanoma, ovarian and oesophageal cancers.  Clinical data, to date, demonstrate encouraging rates of clinical responses and an acceptable tolerability profile.

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14:05-15:35 Use of genetically modified T-cells in treatment of cancer

Professor Carl June, University of Pennsylvania, USA

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15:45-16:15 Cell therapies as medicines

Dr Patrick Vallance, GlaxoSmithKline plc, UK


In oncology and in some genetic diseases it is now clear that genetically manipulated cells have the potential to provide long lasting treatment responses. There is also promise in many other disease areas and a growing confidence that advances in cell/gene therapies will provide an important new treatment option beyond small molecules and biopharmaceutical drugs.  Unlike the traditional areas of drug discovery and development, most of the early discovery work, construction of the “medicine”, and the clinical experiments are taking place within academic settings. This is opening up a rapidly expanding range of opportunities, but also raises a challenge: how can these treatments be made available more widely? There are questions about production, quality control, short and long term safety, measurement of effect, patient selection and monitoring, regulatory requirements, and costs to the healthcare systems around the world. In this talk I will outline some of the cell and gene therapies that are being worked on at GSK (in rare diseases and cancer) and across industry and discuss the approaches being taken to turn cell treatments into viable therapeutic options that can be used globally.

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Cells: from Robert Hooke to Cell Therapy – a 350 year journey

5-6 October 2015

The Royal Society, London 6-9 Carlton House Terrace London SW1Y 5AG UK